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Induction of Th2 responses in infectious diseases
Induction of Th2 responses in infectious diseases Edward J Pearce and Steven L Reiner C o r n e l l University, Ithaca and U n i v e r s i t y of C h i c a g o , C h i c a g o , USA
Recent work on T-helper (Th) cell subset maturation has focused on defining the cellular source of early IL-4, which promotes precursor (naive) CD4 + Th cells to differentiate into Th type 2 (Th2) cells, and also on the roles of counter-regulatory cytokines, costimulatory signals, and antigen in the induction of Th2 responses. Results suggest that not all Th2 cells are equivalent in their ontogeny. Current Opinion in Immunology 1995, 7:497-504 Introduction
The pathway by which CD4 + Th lymphocytes attain effector capabilities involves a post-thymic period of differentiation, initiated by antigen receptor ligation. Following their activation, naive precursor Th cells (ThP), which make only IL-2 in quantity, acquire the ability to secrete discrete panels of cytokines. At least three stable, terminally differentiated types of Th cell are recognized on the basis of the pattern of cytokines that they secrete: Th0, T h l and Th2. In addition to the stable Th0 cell, there is a Th0-like intermediate in the differentiation pathways of both T h l and Th2 cells [1]. The functions of Thl and Th2 cells are better understood than those of Th0 cells, with the T h l cells playing a central role in cell-mediated immunity and the Th2 cells helping humoral immune responses. Owing to the marked counter-regulatory effects of T h l and Th2 subsets and the repetitive antigenic stimulation which characterizes microbial infection, infectious diseases are often characterized by responses highly skewed towards the T h l or Th2 subsets. The development of one response to the exclusion of the other has profound implications for resistance to infection. This is exemplified in several infectious disease models in which the development of pathogen-specific Th2 cells is host strain dependent. Three well characterized models are murine infection with Leishmania major[2], Candida albicans [3] and Trichuris muris [4]. Recently, a similar dichotomy in responses was described in mice infected with Borrelia burgdo~ri, the agent of Lyme disease [5]. In the L. major and candidiasis models, hosts that mount Thl responses are protected, whereas hosts that mount Th2 responses are susceptible to progressive infection. In the T. muris and Lyme disease models the converse is true, and Th2 responses are protective whereas Thl responses are non-protective or, possibly, immunopathologic.
The current review will focus on the key early events involved in the initiation of the primary Th2 response, with emphasis on recent findings from studies of microbial infections. Central to this discussion is the concept that cytokines and signals generated early in the response, possibly as the result of the activation of innate defenses, are instrumental in influencing the subsequent outcome of Th-cell differentiation (Fig. 1).
Does it take IL-4 to make IL-4?
The primary influence in directing the outcome of Th-cell differentiation is the cytokines present in the milieu when the ThP cell is first activated. Over the past few years, it has become clear that IL-12 is the principal cytokine for inducing T h l responses and that the major source of IL-12 during Th cell priming is the macrophage; this area is addressed elsewhere in this issue by Biron and Gazzinelli (10p 485-496). IL-4 is the recognized cytokine promoter of ThP cell differentiation towards the Th2 phenotype, although IL-2 has been implicated as an essential cofactor (reviewed in [6]). Repeated observations indicate that exogenous IL-4 biases cultured ThP cells stimulated with antigen or mitogen to become Th2 cells. Exogenous IL-4 in vivo also promotes Th2 response development, whereas ~this response is prevented by monoclonal antibody (mAb) against IL-4 (reviewed in [6]). Invariably, these interventions have to be made at the time of initial exposure to antigen to be effective. This has led to the to the concept that 'early IL-4' is essential for the initiation of Th2 responses. The development of I L - 4 - / - mice has made possible the definitive examination of the role of IL-4 in Th2 development. Although Th2 responses to Nippostrongylus
Abbreviations APC--antigen-presenting cell; IFN--interferon; IL--interleukin; mAb--monoclonal antibody; r--recombinant; TCR--T-cell receptor; Th--T-helper; Th2--Th type 2; ThP--Th precursor. © Current Biology Ltd ISSN 0952-7915
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positive signal (IL-12) for Thl, or is due to a 'redundant' cytokine like IL-13, which was thought to primarily effect monocytes and B cells [10] but which is capable of signalling via the IL-4 receptor 140 kDa subunit [11°]. The recent findings that naive human T cells activated with anti-CD3 mAb can be prompted to differentiate into Th2 cells by costimulation with anti-CD28 mAb or IL-I~, even under conditions where IL-4 is neutralized, indicate that strong IL-4-independent signals for Th2 differentiation do exist, at least in humans [12°,13°]. The role of these non-IL-4 signals in natural Th2 responses to microorganisms remains to be determined.
brasiliensis are impaired in these animals [7], infection with Plasmodimn chabaudi was recently shown to stimulate, albeit to a lesser extent than in normal mice, the development of a population of Th cells that are Th2-1ike in their ability to make IL-5, IL-6 and IL-10 and to provide help for antibody production [8°]. This response is reminiscent of the residual Th2-1ike response that develops in mice treated extensively with anti-lL-4 mAb during infection with Schistosoma mansoni [9] and in IL-4-/- mice infected with schistosomes (EJ Pearce, unpublished data). Perhaps the weak priming for Th2 responses in the absence of IL-4 is the result of a default pathway that operates in the absence of a strong (a)
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© 1995 Current Opinion in Immunology
Fig. 1. Not all Th2 responses are equivalent in their ontogeny. (a) Pathogens encounter the innate immune system and interact with cells capable of producing early IL-4. The box to the left encloses the various candidate cell types which might contribute early IL-4 for priming Th2 responses. Pathogens might interact with these cell types through a number of unique mechanisms as indicated. Peptide antigens are also processed by APCs, and presented to naive ThP cells. Upon activation there is a transient Th0 state capable of producing multiple cytokines including IL-4, which may also provide a differentiation stimulus for the naive T cell. Other requirements for this pathway of maturation appear to be effective costimulation of the naive ThP and probably the autocrine T cell growth factor IL-2 (not shown). (b) An alternative pathway to arrive at Th2 effector function may be a form of default which features the lack of a strong Thl inducing stimulus, but adequate costimulation and antigen (Ag) activation. This pathway may require some genetic predisposition towards a more Th2-1ike phenotype [19°°]. It is possible that under priming conditions characterized by an absence of a strong Thl stimulus, repetitive antigenic stimulation, which characterizes microbial infection, may direct the ThP into a Th2 configuration. Open arrows represent activation/stimulation steps, shaded arrows indicate differentiation steps.
Induction of Th2 responsesin infectiousdiseasesPearce and Reiner 499 Cellular sources of early IL-4 Although non-T cell sources of IL-4 were thought hkely to be the innate immune system analog of IL-12-secreting macrophages as the 'priming' factor for Th2 development, recent evidence indicates that T cells themselves may be su~icient to produce early IL-4 and thereby initiate and support Th2 effector functions, as the transfer of Th cells alone from naive wild-type mice into I L - 4 - / - recipients allows these animals to subsequently mount an antigen specific IgE response [14"]. In several Th2 model systems [15-17,18"], CD4 + T cells have been the earliest identifiable population to contain IL-4 m R N A or protein. After schistosome egg pulmonary embolization [15], Heligmosomoides polygyrus infection [16], and L. major infection [17], there was a burst of CD4 cell derived IL-4 transcription approximately four days following challenge. In contrast, intracellular IL-4 was evident in peritoneal "~ T cells of N. brasiliensis-infected mice before its appearance in CD4 + cells [18"]. In addition, a transient burst of IL-4 in the peritoneal cell population 2 to 12 hours after the injection ofschistosome eggs into nude mice (EA Sabin, EJ Pearce, unpublished data) supports the hypothesis that a non-Th cell is playing a role in promoting the development of egg-induced Th2 responses. Invoking a CD4+ cell as the source of early IL-4 to drive Th2 differentiation is somewhat paradoxical as many in vitro studies have highlighted the inability of autocrine IL-4 to drive CD4 + cell differentiation [6]. Two recent avenues of investigation may help resolve this paradox. One possibility relates to the aforementioned descriptions of Th2 cells arising in the absence of autocrine or exogenous IL-4. Indeed, it has recently been shown that, when activated in vitro under neutral conditions, ThP cells from some strains of mice (e.g. BALB/c and DBA/2) make inherently more IL-4 and less IFN- T than do ThP cells from other strains (e.g. B10.D2) [19"]. The other explanation may relate to the recent explosion of information regarding the phenotypic heterogeneity of CD4 + cells, which will be discussed now.
compared with conventional CD4 + naive ThP cells, that they are always CD4 + or CD4- CD8-, but never CD8 +, and that they express the NKI.1 surface marker in addition to traditional memory markers such as CD44bright and LECAMdull [22"]. They use a highly restricted T C R repertoire of three predominant V~ regions, V~8, 7 and 2, and an invariant TCR~t chain, Vet 14-J281 [23"] on all M H C backgrounds examined. The monomorphic T C R usage suggested that these cells may be selected on a non-polymorphic restriction element [24"] and, indeed, it has been demonstrated that many are CD1 restricted (A Bendelac, personal communication; D Mathis, personal communication), a finding consistent with their diminution in class I deficient mice and their presence in class II deficient mice [22",25"]. When anti-CD3 mAb is injected into naive mice, IL-4 m R N A is evident in the spleen within 90 minutes and can be segregated to this population of T cells [26"]. In a system more dependent on antigen presentation (i.e. immunization with goat anti-mouse IgD) these cells were also implicated as indispensable for Th2 priming by virtue of the inability of class I deficient mice to express IL-4 or to produce IgE compared with their class I replete controls (T Yoshimoto, A Bendelac, W Paul, personal communication). It is yet to be determined whether the CD4+NKI.1 ÷ population will be implicated as the priming source of IL-4 production in some of the aforementioned situations in which Th2 reponses develop. In fact, at day four, schistosome egg granulomata appear to form normally in mice deficient in class I, and these animals have normal levels of IL-4 (T Wynn, A Sher, personal communication). After L. major infection, class I deficient mice exhibit an intact burst of IL-4, although the effect of this deficiency on Th2 response development in innately susceptible mouse strains, such as BALB/c, is yet to be tested (S Reiner, 1~ Locksley, unpublished data). The characterization of the CD4+NK1.1 + population also leaves open the possibility that other pre-activated populations exist (for example, see [27"]).
Counter-regulation and costimulation CD4 + cells that might initiate Th2 responses It has been recognized for some time that immunologically naive mice have subpopulations of T cells that are capable of producing mature lymphokines upon initial activation. These cells, which express surface markers characteristic of immunologically experienced lymphocytes, were regarded as 'memory' cells [20] that encountered foreign or self antigens in the periphery, and then became quiescent until their eventual reactivation. The description of a population of recent thymic emigrants with a 'memory' phenotype may help to explain the ontogeny of many of these cells [21]. It is now evident that these cells have an unusual lineage
One of the most important influences of Th2 development described in the past year has been the role of IL-12 in suppressing or converting Th2 responses into Thl responses. Exogenous IL-12 given at the time of schistosome egg injection is able to promote the development of antigen-specific Thl responses while suppressing Th2 responses [28,29]. This inhibition of Th2 responses, though not the promotion of Thl responses, is dependent on IFN-y, as IL-12 fails to have this effect in egg-injected IFN~/-/- mice [30"] or wild-type mice that have been treated with anti-IFN-T mAb [28]. During N. brasiliensis infection, the development of the protective Th2 response and
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Immunityto infection allergy-associated immunological changes (e.g. elevated IgE levels, eosinophilia, mastocytosis) can be markedly inhibited in a manner dependent on IFN- T by the injection of IL-12 within the first two to four days, but not after days six to eight, following infection [31]. These results are similar to the earlier reports of the ability oflL-12 to suppress Th2-cell development in BALB/c mice infected with L. major [32,33]. In some infections, endogenous IL-12 plays an indispensable role in preventing Th2-cell development as shown by the default to Th2 response in murine candidiasis [34,35] or toxoplasmosis [36] when animals are treated with anti-IL-12 mAb. Some paradoxical effects of IL-12 on the regulation of Th2 responses have also been observed. In I F N - y - / - animals challenged with schistosome eggs, IL-12 promoted Th2-associated pathology probably by stimulating the proliferation of very recently activated Th cells [30°']. The concept that IL-12 acts only to hmit Th2 responses can be called into question by this finding and by the description of IL-12 acting to augment IL-4 production during in vitro priming, when IL-4 is also present in high concentrations [37"]. This may be related to IL-12's abihty to increase IL-4 production in a committed Th2 population during L. major infection [38]. O f further interest are the descriptions of IL-12's ability to induce IL-10 from non-T cell populations [28,29,31,38], which may serve a regulatory function by bruiting excessive IL-12 [39]. In some systems, IL-12 may not even be induced directly by the pathogen as has been described in the schistosome egg model: early IFN-y transcription was unaffected by the addition of anti-IL-12 mAb, but levels of early IL-12 were diminished by depletion of natural killer cells or IFN-y [28]. In other systems, IL-12 induction may be delayed or of a magnitude insufficient to suppress early IL-4 production in the manner that pharmacologic recombinant (r)IL-12 is capable of [17,38]. The role of costimulatory molecules in selectively driving Th-cell maturation is an important new area in understanding the requirements for Th2 initiation. Mice deficient in CD28 appear to have intact cellmediated immunity, but impaired humoral responses [40]. Treatment of H. polygyrus-infected mice with the fusion molecule CTLA-4-1g, which blocks the interaction of B7 molecules on antigen-presenting cells (APCs) with CD28 or CTLA-4 on Th cells, inhibited Th2 response development in this system, but only if given before day three following infection [41°]. In L. major-infected BALB/c mice, early transient blockade with CTLA-4-Ig converted the response from a Th2 to a T h l phenotype and had no discernible effect on resistant mice in their ability to heal [42"]. Naive Th cells from TCtk transgenic mice did not acquire the ability to produce IL-4 when activated with antigen-APC in the presence of CTLA-4-Ig unless exogenous IL-2 was added, suggesting that the lesion caused by CTLA-4-Ig addition is a result of inhibition of IL-2 production [43]. As IL-2 transcription has not, however, been
observed to preceed Th2 response development in H. polygyrus infection [16] and was at normal levels in mice infected with L. major [42"], it is possible that the CD28/CTLA-4 costimulatory pathway plays an additional role in allowing Th2-cell differentiation. There is also some evidence to suggest that distinct B7 hgands costimulate preferentially to achieve biased Th phenotype maturation [44"], but this has not yet been extended to a microbial system.
Regulating established Th2 responses With ongoing Th2 responses, and as more antigens progressively immunize the host repertoire over time, IL-4 may act to condition new specificities to become Th2-hke during the process known as epitope spreading. This is particularly relevant to immune responses to microbes which present complex and replicating antigens. During Th2 responses, the expansion of a population ofFcER + cells, which can respond to antigen cross-linked Fctk-bound IgE by secreting large amounts of IL-4, provides a secondary level of amplification for this process. Recent observations [45°] support a notion that these FcgR + cells are the major source of IL-4 in some established Th2 responses. The depletion of serum IgE available for arming these cells could explain the paradoxical finding that anti-IgE mAb causes a diminution in serum IL-4 levels in mice infected with schistosomes [46]. The influence of a pre-existing Th2 response in skewing new specificities towards the Th2 phenotype is not restricted to epitopes within the same pathogen. The development of a Th2 response to bystander antigen may explain why AKtk mice, which normally mount a non-protective Thl response to T. muris, failed to do so and were rendered resistant to this helminth by an established schistosome infection [47"]. The fact that new specificities may become Th2-1ike driven by IL-4 from cell populations primed earlier in the immune response, suggests a potential target for therapeutic intervention. Despite the generally pessimistic findings of the inability ofcytokines to switch the phenotype of established T h l and Th2 clones in in vitro, the in vivo situation, which is often polyclonal, may be a bit more permissive. Indications from natural histories of several models indicate that switching of phenotypes can occur. In schistosomiasis, the larval stage is characterized by a T h l response, which gives way to a Th2 response during egg deposition [48]. In P. chabaudi murine malaria, there is also a switch from a T h l to a Th2 response [49]. Additionally, a switch from a dominant Thl response to one characterized by the production of IL-4 has been noted to occur during the progression of HIV infection [50]. In L. major infection, interventions (e.g. anti-IL-4 mAb) capable of reversing estabhshed Th2 responses of BALB/c mice have not been successful when administered after two weeks, but when combined with pentavalent antimony, both
Induction of Th2 responsesin infectiousdiseasesPearce and Reiner anti-IL-4 and rlL-12 were capable of causing a Th2 to T h l switch [51,52]. Similarly, polyclonal Th-cell lines from resistant mice were switched from a Thl to Th2 phenotype ex vivo using rlL-4 [53]. Using priming of transgenic T cells, after long-term stimulation, the T cells become more immutable, akin to established clones. Within the first one or two rounds of stimulation, however, the phenoytpes can be interconverted by cytokines (A O'Garra, personal communication).
Antigen dose and form influence Th subset selection One of the increasingly recognized variables in the successful initiation of Th2 responses appears to be the amount of priming antigen. The important work of Parish and Liew in 1972 [54] presaged recent work in the T. muris [55 °] and L. major systems [56], in which if the host strain that typically mounts a Th2 response is challenged with a low number of organisms, the response becomes Thl-like instead. This is not merely due to the net effect of lowered virulence as in the T. muffs model, Thl response correlates to susceptibility, and despite the reduction in inocula, the erstwhile innately 'resistant animal becomes susceptible [55°]. This is consistent with findings in transgenic T cells that higher peptide doses favored increased IL-4 production (A O'Garra, personal communication), and is perhaps consistent with an overall model that a Th2 response requires optimal avidity on many levels, including costimulation, growth factors (such as IL-2), and antigen dose. Such a model might partly explain the recently demonstrated requirement for B cells in the P. chabaudi-induced Th2 response [49], as these cells would be likely to generate high ligand density during antigen presentation. These views are somewhat at variance, however, with the recent findings that stronger T C R - M H C interaction favors a T h l response but weaker interaction favors a Th2 response in at least one model system [57]. The discrepancy may be partly explained by the earlier observation that the reciprocal dominance of ceU-mediated and humoral immunity shifts more than one time over a dose response of immunization [54]. Variables, such as route of administration, can also play a role in directing Th development, either by eliciting unique patterns of cytokines[58], inducing tolerance versus immunity [59], or perhaps through another, undefined mechanism. The form of the antigen, whether soluble (Thl-favoring) or particulate (Th2-favoring) [60], might also be an important influence in the type of response elicited by microbial stimuli. Although peptide antigens are considered the critical immunogens for driving specific T-cell responses, sugars and lipids may be equally important if they can make the necessary and sufficient 'adjustments' to the innate
milieu to direct biased Th development. Two molecules that stimulate monocytes/macrophages to make IL-12, and thus might augment T h l induction, have been identified. One of these, surprisingly, is the L. braziliensis homologue of elongation initiation factor 4A [61], while the other is the glycosylated lipid lipopolysaccharide. The observations that certain helminths, for example H. polygyrus, or particular helminth life-cycle stages, such as the schistosome egg, invariably induce Th2 responses has led to the suggestion that these organisms contain molecules that predispose the immune response to become Th2 like, perhaps by preferentially stimulating the production of IL-4 by one of the Th2-inducing populations discussed above. Pertinent to this point is the recent observation that a saccharide, lacto-N-fucopentaose III (LNFP-III), found on schistosome egg antigenic glycoproteins, directly induces IL-10 production in B cells [62]. By downregulating cytokine secretion by T h l cells, IL-10 could contribute to the overall Th2 dominance observed in immune responses to eggs. An additional unexpected facet to this story is the realization that T cells may also be capable of activation by atypical non-peptide epitopes. Recent description [63] of specificity for carbohydrate-modified peptides in the context of conventional class I restriction, a well characterized mycolic acid (lipid)-specific, CDl-restricted T-cell clone from a patient with tuberculosis [64 "°] and y8 T cells that recognize non-peptide antigens [65] provide increasing weight to the notion that our understanding of T-cell recognition during imnmne responses is not complete.
Conclusion The recent study of infectious disease models has provided insight into the requirements for developing Th2-type effector cells. Clearly IL-4 is a key cytokine for the induction of a Th2 response in many instances, but the source of IL-4 crucial for Th2 priming remains unclear in the majority of cases. There is considerable interest as to whether CD4 + NKI.1 + cells or similar pre-activated cells may be the elusive cellular source of early IL-4. The newly recognized potential for "non-conventional interactions between microbial ligands and immune cells has increased the excitement, albeit the complexity of the field. The finding that costimulation and other interactions that strengthen the response are virtually indispensable in promoting Th2 subset development holds promise for elucidating the molecular events that lead an uncommitted Th cell to differentiate in this manner.
Note added in proof Since the submission of this article, two more relevant papers have been published [66,67].
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Yoshimoto T, Paul WE: CD4P% NKI.lP ~ T cells promptly produce interleukin 4 in response 1o in vivo challenge with anti-CD3. J Exp Med 1994, 179:1285-1295. Indicates potentially critical role of this cell population in shaping T-helper cell type 2 responses in vivo, and as the early source of IL-4 after injection of anti-CD3. 27. •
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Oswald IP, Caspar P, Jankovic D, Wynn TA, Pearce EJ, Sher A: IL-12 inhibits Th2 cytoklne responses induced by eggs of Schistosoma mansoni. ] Immunol 1994, 153:1707-1713.
30. ••
Wynn TA, Jankovic D, Hieny S, Zioncheck K, Jardieu P, Cheever AW, Sher A: IL-12 exacerbates rather than suppresses T helper 2-dependent pathology in the absence of endogenous IFN-y. J Immunol 1995, 154:39994009. With [37••], suggests that a major underlying function of IL-12 is as a T cell growth factor, and that its ability to allow T-helper cell type 1 (Thl) expansion to the detriment of Th2 responses is indirect, and due to its ability to promote IFN-y production. 31.
Finkelman FD, Madden KB, Cheever AW, Katona IM, Morris SC, Gately MK, Hubbard BR, Gause WC, Urban JF Jr: Effects of interleukin 12 on immune responses and host protection in mice infected with intestinal nematode parasites. J Exp Med 1994, 179:1563-1572.
32.
Heinzel FP, Schoenhaut DS, Rerko RM, Rosser LE, Gately MK: Recombinant interleukin 12 cures mice infected with Leishmania major. J Exp Med 1993, 177:1505-1509.
33.
Sypek JP, Chung CL, Mayor SEH, Subramanyam JM, Goldman SJ, Sieburth DS, Wolf SF, Schaub RG: Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response. J Exp Med 1993, 177:1797-1802.
34.
Romani L, Mencacci A, Tonnetti L, Spaccapelo R, Cenci E, Puccetti P, Wolf SF, Bistoni F: IL-12 is both required and prognostic in vivo for T helper type 1 differentiation in murine candldiasls. J Immunol 1994, 152:5167-5175.
35.
Romani L, Mencacci A, Tonnetti L, Spaccapelo R, Cenci E, Wolf S, Puccetti P, Bistoni F: Interleukin-12 but not interferon-y production correlates with induction of T helper type.1 phenotype in murine candidiasis. Eur ] Immunol 1994, 24:909-915.
36.
Gazzinelli RT, Wysocka M, Hayashi S, Denkers EY, Hieny S, Caspar P, Trinchieri G, Sher A: Parasite-induced IL-12 stimulates early IFN-y synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol 1994, 153:2533-2543.
37. ••
Schmitt E, Hoehn P, Germann T, RCide E: Differential effects of interleukin-12 on the development of naive mouse CD4 + T cells. Eur J/mmuno/ 1994, 24:343-347. Very intriguing study that shows that T cells optimally primed by IL-4 have augmented, rather than diminished, IU4 production upon the addition of IL-12. Curiously, the mouse strain used is BALB/c, which develops a T-belper type 2 response to Leishmania major infection, a priming system characterized by both early IL-4 and IL-12. 38.
Wang Z-E, Zheng S, Corry DB, Dalton DK, Seder RA, Reiner SL, Locksley RM: Interferon y-independent effects of interleukin 12 administered during acute or established infection due to Leishmania major. Proc Nat/ Acad Sci USA 1994, 91:12932-12936.
39.
Kennedy MK, Picha KS, Shanebeck KD, Anderson DM, Grabstein KH: Interleukin-12 regulates the proliferation of Thl, bul nol Th2 or Th0, clones. Eur J Immunol 1994, 24:2271-2278.
40.
Shahinian A, Pfeffer K, Lee KP, K0ndig TM, Kishihara K, Wakeham A, Kawai K, Ohashi PS, Thompson CB, Mak TW: Differential T cell costimulatory requirements in CD28-deflcient mice. Science 1993, 261:609~12.
41. •
Lu P, Zhou XD, Chen S-J, Moorman M, Morris SC, Finkelman FD, Linsley P, Urban JF, Gause WC: CTLA-4 ligands are required to induce an in vlvo interleukin 4 response to a gastrointestinal nematode parasite. J Exp Med 1994, 180:693~o98. Strongly implicates the CD28/CTLA-4 signalling pathway as playing an important role in promoting the differentiation of precursor T-helper (Th) cell to Th type 2 cells. Complements [12",13*,42",44•]. 42. •
Corry DB, Reiner SL, Linsley PS, Locksley RM: Differential effects of blockade of CD28-B7 on the development of Thl or Th2 effector cells in experimental leishmaniasis. J Immunol 1994, 153:4142-4148. Along with [41•], provides very important evidence that more than IL-4 is required to successfully generate a T-helper (Th) type 2 response. Although costimulation was required to initiate a Th2 response in BALB/c mice, it was not required to initiate a Thl response in susceptible or resistant strains, a result reminiscent of the role of IL-2 and altered antigen dose early in this model. 43.
Seder RA, Germain RN, Linsley PS, Paul WE: CD28-mediated costimulation of interleukin 2 (IL-2) production plays a critical role in T cell priming for It-4 and interferon y production. J Exp Med 1994, 179:299-304.
44. •
Kuchroo VK, Das MP, Brown JA, Ranger AM, Zamvill SS, Sobel RA, Weiner HL, Nabavi N, Glimcher LH: B7-1 and B7-2 costimulatory molecules activate differentially the Thl/Th2 developmental pathways: application to autoimmune disease therapy. Cell 1995, 80:707-718. Interesting view that selective T-helper (Th) cell differentiation pathways are promoted by distinct B7 ligands. Using the experimental autoimmune encephalomyelitis model, anti-B7-1 was protective (by limiting Th type 1 [Thl] responses) and anti-B7-2 worsened disease (by attenuating Th2 reponses). The therapeutic effects were less dramatic at the extreme ends of the disease spectrum. This dichotomy has not yet been extended to microbial models, where more polarized responses are often induced. 45. •
Aoki I, Kinzer C, Shirai A, Paul WE, Klinman DM: IgE receptor-positive non-B/non-T cells dominate the production of interleukln 4 and interleukln 6 in immunized mice. Proc Nat/Acad Sci USA 1995, 92:2534-2538. Suggests that non-B/non-T cells positive for IgE receptor may subsume some of the effector functions of T-helper type 2 (Th2) cells and participate in a positive feedback loop to perpetuate and expand Th2 responses. 46.
Amiri P, Haak-Frendscho M, Robbins K, McKerrow JH, Stewart T, Jardieu P: Anti-immunoglobulin E treatment decreases worm burden and egg production in Schistoma mansoni infected normal and interferon-y knockout mice. J Exp Med 1994, 180:43-51.
47. •
Curry AJ, Else KJ, Jones F, Bancroft A, Grencis RK, Dunne DW: Evidence that cytokine-mediated immune interactions induced by Schist@soma mansoni alter disease outcome in mice concurrently infected with Trfchuris muds. J Exp Med 1995, 181:769-774. AKR mice, which normally mount a non-protective T-helper cell type 1 (Thl) response to the intestinal helminth T. muris, were rendered resistant to infection with this parasite by a pre-existing Th2 response induced by schistosome eggs. This probably represents the influence of if-4 from the schistosome-specific Th2 response in skewing new T. muris specificities ('heterologous epitope spreading') towards the Th2 phenotype. 48.
Pearce EJ, Caspar P, Grzych JM, Lewis FA, Sher A: Downregulation of Thl cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schlst@soma mansoni. J Exp Med 1991, 173:159-166.
49.
Taylor-Robinson AW, Phillips RS: B cells are required for the switch from Thl- to Th2-regulated immune responses to
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I m m u n i t y t o infection Plasmodium chabaudl chabaudi infection. Infect Immun 1994, 62:2490-2498.
50.
Cleriei M, Shearer GM: The Thl-Th2 hypothesis of HIV infection: new insights. Immunol Today 1994, 15:575-581.
51.
Nabors GS, Farrell JP: Depletion of interleukin-4 in BALB/c mice with established Leishmanla major infections increases the efficacy of antimony therapy and promotes Thl-like responses. Infect Immun 1994, 62:5498-5504.
52.
Nabors GS, Afonso LCC, Farrell JP, Scott P: Switch from a type 2 to a type 1 T helper cell response and cure of established Lelshmanla major infection in mice is induced by combined therapy with interleukin 12 and pentostam. Proc Natl Acad Sci USA 1995, 92:3142-3146.
53.
Mocci S, Coffman RL: Induction of a Th2 population from a polarized Lelshmania-speciflc Thl population by in vitro culture with IL-4. J Immunol 1995, 154:3779-3787.
54.
ParishCR, Liew FY: Immune response to chemically modified flagellin. J Exp Med 1972, 135:298-311.
55. •
Bancroft AJ, Else KJ, Greneis RK: Low-level infection with Trfchuri$ muds significantly affects the polarization of the CD4 response. Eur J Immunol 1994, 24:3113-3118. Excellent example of how antigen dose can effect subset selection. Along with [56], lends weight to the hypothesis that large antigen load predisposes towards T-helper cell type 2 responses. This is an infectious disease example of Parrish and Liew's original observation (see also [54]). 56.
Bretscher PA, Wei G, Menon JN, Bielefeldt-Ohmann H: Establishment of stable, cell-mediated immunity that makes 'susceptible' mice resistant to Lelshmania major. Science 1992, 257:539-542.
57.
Pfeiffer C, Stein J, Southwood S, Ketelaar H, Sette A, Bottomly K: Altered peptide ligands can control CD4 T lymphocyte differentiation in vivo. J Exp Med 1995, 181:1569-1574.
58.
Williams ME, Caspar P, Oswald I, Sharma HK, Pankewycz O, Sher A, James SL: Vaccination routes that fail to elicit protective immunity against Schistosoma mansonl induce the production of TGF-~ which downregulates macrophage antiparasitic activity. J Immunol 1995, 154:4693-4700.
59.
Aebischer T, Morris L, Handman E: Intravenous injection of irradiated Leishmania major into susceptible BALB/c mice: immunization or protective tolerance. Int Immunol 1994, 6:1535-1543.
60.
Kurup VP, Seymour BWP, Choi H, Coffman RL: Particulate Aspergillus fumigatus antigens elicit a TH2 response in BALB/c mice. J Allergy Clin Immunol 1994, 93:1013-1020.
61.
Skeiky YAW, Guderian JA, Benson DR, Bacelar O, Carvalho EM, Kubin M, Badaro R, Trinchieri G, Reed SG: A recombinant
Lelshmanla antigen that stimulates human peripheral blood mononuclear cells to express a Thl-type cytokine profile and to produce interleukin 12. J Exp Med 1995, 181:1527-1537.
62.
Velupillai P, Ham DA: Oligosaccharide-specific induction of interleukin 10 production by B220+ cells from schistosomeinfected mice: a mechanism for regulation of CD4 + T-cell subsets. Proc Nat/ Acad Sci USA 1994, 91:18-22.
63.
Haurum JS, Arsequell G, Lellouch AC, Wong SYC, Dwek RA, McMichael AJ, Elliott T: Recognition of carbohydrate by major histocompatibility complex class I-restricted, glycopeptlde-specific cytotoxic T lymphocytes. J Exp Med 1994, 180:739-744.
64. ""
Beckman EM, Porcelli SA, Morita CT, Behar SM, Eurloong ST, Brenner MB: Recognition of a lipid antigen by CDl-restricted crib+ T cells. Nature 1994, 372:691~94. Highlights the emerging concept that atypical antigens (lipid) and non-classical restriction elements (CD1) might interact with unusual lymphocytes (CD4-,CD8-) in real infectious diseases of humans (tuberculosis). Likely to be an extremely important area of investigation in the next few years. 65.
Bukowski JF, Morita CT, Tanaka Y, Bloom BR, Brenner MB, Band H: Vy2V82 TCR-dependent recognition of non-peptide antigens and daudi cells analyzed by TCR gene transfer. J Immunol 1995, 154:998-1006.
66.
Bendelac SA, Lantz O, Quimby ME Yewdell JW, Bennink JR,
Brutkiewicz RR: CD1 recognition by mouse NKI ÷ lymphocytes. Science 1995, 268:863-865. 67.
Sieling PA, Chatterjee D, Porcelli SA, Prigozy RJ, Mazzaccaro RJ, Soriano T, Bloom BR, Brenner MB, Kronenberg M, Brennan PJ, Modlin RL. CDl-restricted T cell recognition of microbial lipoglycan antigens. Science 369:227-230.
EJ Pearce, Department of Microbiology, Immunology and Parasitology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853-6401, USA. E-mail:[email protected] SL Reiner, Gwen Knapp Center for Lupus and Immunology Research, Department of Medicine and Committee on Immunology, University of Chicago, 924 East 57th Street, Chicago, Illinois 60637-5420, USA. E-mail:[email protected] Author for correspondence: EJ Pearce.
Recent work on T-helper (Th) cell subset maturation has focused on defining the cellular source of early IL-4, which promotes precursor (naive) CD4 + Th cells to differentiate into Th type 2 (Th2) cells, and also on the roles of counter-regulatory cytokines, costimulatory signals, and antigen in the induction of Th2 responses. Results suggest that not all Th2 cells are equivalent in their ontogeny. Current Opinion in Immunology 1995, 7:497-504 Introduction
The pathway by which CD4 + Th lymphocytes attain effector capabilities involves a post-thymic period of differentiation, initiated by antigen receptor ligation. Following their activation, naive precursor Th cells (ThP), which make only IL-2 in quantity, acquire the ability to secrete discrete panels of cytokines. At least three stable, terminally differentiated types of Th cell are recognized on the basis of the pattern of cytokines that they secrete: Th0, T h l and Th2. In addition to the stable Th0 cell, there is a Th0-like intermediate in the differentiation pathways of both T h l and Th2 cells [1]. The functions of Thl and Th2 cells are better understood than those of Th0 cells, with the T h l cells playing a central role in cell-mediated immunity and the Th2 cells helping humoral immune responses. Owing to the marked counter-regulatory effects of T h l and Th2 subsets and the repetitive antigenic stimulation which characterizes microbial infection, infectious diseases are often characterized by responses highly skewed towards the T h l or Th2 subsets. The development of one response to the exclusion of the other has profound implications for resistance to infection. This is exemplified in several infectious disease models in which the development of pathogen-specific Th2 cells is host strain dependent. Three well characterized models are murine infection with Leishmania major[2], Candida albicans [3] and Trichuris muris [4]. Recently, a similar dichotomy in responses was described in mice infected with Borrelia burgdo~ri, the agent of Lyme disease [5]. In the L. major and candidiasis models, hosts that mount Thl responses are protected, whereas hosts that mount Th2 responses are susceptible to progressive infection. In the T. muris and Lyme disease models the converse is true, and Th2 responses are protective whereas Thl responses are non-protective or, possibly, immunopathologic.
The current review will focus on the key early events involved in the initiation of the primary Th2 response, with emphasis on recent findings from studies of microbial infections. Central to this discussion is the concept that cytokines and signals generated early in the response, possibly as the result of the activation of innate defenses, are instrumental in influencing the subsequent outcome of Th-cell differentiation (Fig. 1).
Does it take IL-4 to make IL-4?
The primary influence in directing the outcome of Th-cell differentiation is the cytokines present in the milieu when the ThP cell is first activated. Over the past few years, it has become clear that IL-12 is the principal cytokine for inducing T h l responses and that the major source of IL-12 during Th cell priming is the macrophage; this area is addressed elsewhere in this issue by Biron and Gazzinelli (10p 485-496). IL-4 is the recognized cytokine promoter of ThP cell differentiation towards the Th2 phenotype, although IL-2 has been implicated as an essential cofactor (reviewed in [6]). Repeated observations indicate that exogenous IL-4 biases cultured ThP cells stimulated with antigen or mitogen to become Th2 cells. Exogenous IL-4 in vivo also promotes Th2 response development, whereas ~this response is prevented by monoclonal antibody (mAb) against IL-4 (reviewed in [6]). Invariably, these interventions have to be made at the time of initial exposure to antigen to be effective. This has led to the to the concept that 'early IL-4' is essential for the initiation of Th2 responses. The development of I L - 4 - / - mice has made possible the definitive examination of the role of IL-4 in Th2 development. Although Th2 responses to Nippostrongylus
Abbreviations APC--antigen-presenting cell; IFN--interferon; IL--interleukin; mAb--monoclonal antibody; r--recombinant; TCR--T-cell receptor; Th--T-helper; Th2--Th type 2; ThP--Th precursor. © Current Biology Ltd ISSN 0952-7915
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Immunity to infection
positive signal (IL-12) for Thl, or is due to a 'redundant' cytokine like IL-13, which was thought to primarily effect monocytes and B cells [10] but which is capable of signalling via the IL-4 receptor 140 kDa subunit [11°]. The recent findings that naive human T cells activated with anti-CD3 mAb can be prompted to differentiate into Th2 cells by costimulation with anti-CD28 mAb or IL-I~, even under conditions where IL-4 is neutralized, indicate that strong IL-4-independent signals for Th2 differentiation do exist, at least in humans [12°,13°]. The role of these non-IL-4 signals in natural Th2 responses to microorganisms remains to be determined.
brasiliensis are impaired in these animals [7], infection with Plasmodimn chabaudi was recently shown to stimulate, albeit to a lesser extent than in normal mice, the development of a population of Th cells that are Th2-1ike in their ability to make IL-5, IL-6 and IL-10 and to provide help for antibody production [8°]. This response is reminiscent of the residual Th2-1ike response that develops in mice treated extensively with anti-lL-4 mAb during infection with Schistosoma mansoni [9] and in IL-4-/- mice infected with schistosomes (EJ Pearce, unpublished data). Perhaps the weak priming for Th2 responses in the absence of IL-4 is the result of a default pathway that operates in the absence of a strong (a)
(b)
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© 1995 Current Opinion in Immunology
Fig. 1. Not all Th2 responses are equivalent in their ontogeny. (a) Pathogens encounter the innate immune system and interact with cells capable of producing early IL-4. The box to the left encloses the various candidate cell types which might contribute early IL-4 for priming Th2 responses. Pathogens might interact with these cell types through a number of unique mechanisms as indicated. Peptide antigens are also processed by APCs, and presented to naive ThP cells. Upon activation there is a transient Th0 state capable of producing multiple cytokines including IL-4, which may also provide a differentiation stimulus for the naive T cell. Other requirements for this pathway of maturation appear to be effective costimulation of the naive ThP and probably the autocrine T cell growth factor IL-2 (not shown). (b) An alternative pathway to arrive at Th2 effector function may be a form of default which features the lack of a strong Thl inducing stimulus, but adequate costimulation and antigen (Ag) activation. This pathway may require some genetic predisposition towards a more Th2-1ike phenotype [19°°]. It is possible that under priming conditions characterized by an absence of a strong Thl stimulus, repetitive antigenic stimulation, which characterizes microbial infection, may direct the ThP into a Th2 configuration. Open arrows represent activation/stimulation steps, shaded arrows indicate differentiation steps.
Induction of Th2 responsesin infectiousdiseasesPearce and Reiner 499 Cellular sources of early IL-4 Although non-T cell sources of IL-4 were thought hkely to be the innate immune system analog of IL-12-secreting macrophages as the 'priming' factor for Th2 development, recent evidence indicates that T cells themselves may be su~icient to produce early IL-4 and thereby initiate and support Th2 effector functions, as the transfer of Th cells alone from naive wild-type mice into I L - 4 - / - recipients allows these animals to subsequently mount an antigen specific IgE response [14"]. In several Th2 model systems [15-17,18"], CD4 + T cells have been the earliest identifiable population to contain IL-4 m R N A or protein. After schistosome egg pulmonary embolization [15], Heligmosomoides polygyrus infection [16], and L. major infection [17], there was a burst of CD4 cell derived IL-4 transcription approximately four days following challenge. In contrast, intracellular IL-4 was evident in peritoneal "~ T cells of N. brasiliensis-infected mice before its appearance in CD4 + cells [18"]. In addition, a transient burst of IL-4 in the peritoneal cell population 2 to 12 hours after the injection ofschistosome eggs into nude mice (EA Sabin, EJ Pearce, unpublished data) supports the hypothesis that a non-Th cell is playing a role in promoting the development of egg-induced Th2 responses. Invoking a CD4+ cell as the source of early IL-4 to drive Th2 differentiation is somewhat paradoxical as many in vitro studies have highlighted the inability of autocrine IL-4 to drive CD4 + cell differentiation [6]. Two recent avenues of investigation may help resolve this paradox. One possibility relates to the aforementioned descriptions of Th2 cells arising in the absence of autocrine or exogenous IL-4. Indeed, it has recently been shown that, when activated in vitro under neutral conditions, ThP cells from some strains of mice (e.g. BALB/c and DBA/2) make inherently more IL-4 and less IFN- T than do ThP cells from other strains (e.g. B10.D2) [19"]. The other explanation may relate to the recent explosion of information regarding the phenotypic heterogeneity of CD4 + cells, which will be discussed now.
compared with conventional CD4 + naive ThP cells, that they are always CD4 + or CD4- CD8-, but never CD8 +, and that they express the NKI.1 surface marker in addition to traditional memory markers such as CD44bright and LECAMdull [22"]. They use a highly restricted T C R repertoire of three predominant V~ regions, V~8, 7 and 2, and an invariant TCR~t chain, Vet 14-J281 [23"] on all M H C backgrounds examined. The monomorphic T C R usage suggested that these cells may be selected on a non-polymorphic restriction element [24"] and, indeed, it has been demonstrated that many are CD1 restricted (A Bendelac, personal communication; D Mathis, personal communication), a finding consistent with their diminution in class I deficient mice and their presence in class II deficient mice [22",25"]. When anti-CD3 mAb is injected into naive mice, IL-4 m R N A is evident in the spleen within 90 minutes and can be segregated to this population of T cells [26"]. In a system more dependent on antigen presentation (i.e. immunization with goat anti-mouse IgD) these cells were also implicated as indispensable for Th2 priming by virtue of the inability of class I deficient mice to express IL-4 or to produce IgE compared with their class I replete controls (T Yoshimoto, A Bendelac, W Paul, personal communication). It is yet to be determined whether the CD4+NKI.1 ÷ population will be implicated as the priming source of IL-4 production in some of the aforementioned situations in which Th2 reponses develop. In fact, at day four, schistosome egg granulomata appear to form normally in mice deficient in class I, and these animals have normal levels of IL-4 (T Wynn, A Sher, personal communication). After L. major infection, class I deficient mice exhibit an intact burst of IL-4, although the effect of this deficiency on Th2 response development in innately susceptible mouse strains, such as BALB/c, is yet to be tested (S Reiner, 1~ Locksley, unpublished data). The characterization of the CD4+NK1.1 + population also leaves open the possibility that other pre-activated populations exist (for example, see [27"]).
Counter-regulation and costimulation CD4 + cells that might initiate Th2 responses It has been recognized for some time that immunologically naive mice have subpopulations of T cells that are capable of producing mature lymphokines upon initial activation. These cells, which express surface markers characteristic of immunologically experienced lymphocytes, were regarded as 'memory' cells [20] that encountered foreign or self antigens in the periphery, and then became quiescent until their eventual reactivation. The description of a population of recent thymic emigrants with a 'memory' phenotype may help to explain the ontogeny of many of these cells [21]. It is now evident that these cells have an unusual lineage
One of the most important influences of Th2 development described in the past year has been the role of IL-12 in suppressing or converting Th2 responses into Thl responses. Exogenous IL-12 given at the time of schistosome egg injection is able to promote the development of antigen-specific Thl responses while suppressing Th2 responses [28,29]. This inhibition of Th2 responses, though not the promotion of Thl responses, is dependent on IFN-y, as IL-12 fails to have this effect in egg-injected IFN~/-/- mice [30"] or wild-type mice that have been treated with anti-IFN-T mAb [28]. During N. brasiliensis infection, the development of the protective Th2 response and
500
Immunityto infection allergy-associated immunological changes (e.g. elevated IgE levels, eosinophilia, mastocytosis) can be markedly inhibited in a manner dependent on IFN- T by the injection of IL-12 within the first two to four days, but not after days six to eight, following infection [31]. These results are similar to the earlier reports of the ability oflL-12 to suppress Th2-cell development in BALB/c mice infected with L. major [32,33]. In some infections, endogenous IL-12 plays an indispensable role in preventing Th2-cell development as shown by the default to Th2 response in murine candidiasis [34,35] or toxoplasmosis [36] when animals are treated with anti-IL-12 mAb. Some paradoxical effects of IL-12 on the regulation of Th2 responses have also been observed. In I F N - y - / - animals challenged with schistosome eggs, IL-12 promoted Th2-associated pathology probably by stimulating the proliferation of very recently activated Th cells [30°']. The concept that IL-12 acts only to hmit Th2 responses can be called into question by this finding and by the description of IL-12 acting to augment IL-4 production during in vitro priming, when IL-4 is also present in high concentrations [37"]. This may be related to IL-12's abihty to increase IL-4 production in a committed Th2 population during L. major infection [38]. O f further interest are the descriptions of IL-12's ability to induce IL-10 from non-T cell populations [28,29,31,38], which may serve a regulatory function by bruiting excessive IL-12 [39]. In some systems, IL-12 may not even be induced directly by the pathogen as has been described in the schistosome egg model: early IFN-y transcription was unaffected by the addition of anti-IL-12 mAb, but levels of early IL-12 were diminished by depletion of natural killer cells or IFN-y [28]. In other systems, IL-12 induction may be delayed or of a magnitude insufficient to suppress early IL-4 production in the manner that pharmacologic recombinant (r)IL-12 is capable of [17,38]. The role of costimulatory molecules in selectively driving Th-cell maturation is an important new area in understanding the requirements for Th2 initiation. Mice deficient in CD28 appear to have intact cellmediated immunity, but impaired humoral responses [40]. Treatment of H. polygyrus-infected mice with the fusion molecule CTLA-4-1g, which blocks the interaction of B7 molecules on antigen-presenting cells (APCs) with CD28 or CTLA-4 on Th cells, inhibited Th2 response development in this system, but only if given before day three following infection [41°]. In L. major-infected BALB/c mice, early transient blockade with CTLA-4-Ig converted the response from a Th2 to a T h l phenotype and had no discernible effect on resistant mice in their ability to heal [42"]. Naive Th cells from TCtk transgenic mice did not acquire the ability to produce IL-4 when activated with antigen-APC in the presence of CTLA-4-Ig unless exogenous IL-2 was added, suggesting that the lesion caused by CTLA-4-Ig addition is a result of inhibition of IL-2 production [43]. As IL-2 transcription has not, however, been
observed to preceed Th2 response development in H. polygyrus infection [16] and was at normal levels in mice infected with L. major [42"], it is possible that the CD28/CTLA-4 costimulatory pathway plays an additional role in allowing Th2-cell differentiation. There is also some evidence to suggest that distinct B7 hgands costimulate preferentially to achieve biased Th phenotype maturation [44"], but this has not yet been extended to a microbial system.
Regulating established Th2 responses With ongoing Th2 responses, and as more antigens progressively immunize the host repertoire over time, IL-4 may act to condition new specificities to become Th2-hke during the process known as epitope spreading. This is particularly relevant to immune responses to microbes which present complex and replicating antigens. During Th2 responses, the expansion of a population ofFcER + cells, which can respond to antigen cross-linked Fctk-bound IgE by secreting large amounts of IL-4, provides a secondary level of amplification for this process. Recent observations [45°] support a notion that these FcgR + cells are the major source of IL-4 in some established Th2 responses. The depletion of serum IgE available for arming these cells could explain the paradoxical finding that anti-IgE mAb causes a diminution in serum IL-4 levels in mice infected with schistosomes [46]. The influence of a pre-existing Th2 response in skewing new specificities towards the Th2 phenotype is not restricted to epitopes within the same pathogen. The development of a Th2 response to bystander antigen may explain why AKtk mice, which normally mount a non-protective Thl response to T. muris, failed to do so and were rendered resistant to this helminth by an established schistosome infection [47"]. The fact that new specificities may become Th2-1ike driven by IL-4 from cell populations primed earlier in the immune response, suggests a potential target for therapeutic intervention. Despite the generally pessimistic findings of the inability ofcytokines to switch the phenotype of established T h l and Th2 clones in in vitro, the in vivo situation, which is often polyclonal, may be a bit more permissive. Indications from natural histories of several models indicate that switching of phenotypes can occur. In schistosomiasis, the larval stage is characterized by a T h l response, which gives way to a Th2 response during egg deposition [48]. In P. chabaudi murine malaria, there is also a switch from a T h l to a Th2 response [49]. Additionally, a switch from a dominant Thl response to one characterized by the production of IL-4 has been noted to occur during the progression of HIV infection [50]. In L. major infection, interventions (e.g. anti-IL-4 mAb) capable of reversing estabhshed Th2 responses of BALB/c mice have not been successful when administered after two weeks, but when combined with pentavalent antimony, both
Induction of Th2 responsesin infectiousdiseasesPearce and Reiner anti-IL-4 and rlL-12 were capable of causing a Th2 to T h l switch [51,52]. Similarly, polyclonal Th-cell lines from resistant mice were switched from a Thl to Th2 phenotype ex vivo using rlL-4 [53]. Using priming of transgenic T cells, after long-term stimulation, the T cells become more immutable, akin to established clones. Within the first one or two rounds of stimulation, however, the phenoytpes can be interconverted by cytokines (A O'Garra, personal communication).
Antigen dose and form influence Th subset selection One of the increasingly recognized variables in the successful initiation of Th2 responses appears to be the amount of priming antigen. The important work of Parish and Liew in 1972 [54] presaged recent work in the T. muris [55 °] and L. major systems [56], in which if the host strain that typically mounts a Th2 response is challenged with a low number of organisms, the response becomes Thl-like instead. This is not merely due to the net effect of lowered virulence as in the T. muffs model, Thl response correlates to susceptibility, and despite the reduction in inocula, the erstwhile innately 'resistant animal becomes susceptible [55°]. This is consistent with findings in transgenic T cells that higher peptide doses favored increased IL-4 production (A O'Garra, personal communication), and is perhaps consistent with an overall model that a Th2 response requires optimal avidity on many levels, including costimulation, growth factors (such as IL-2), and antigen dose. Such a model might partly explain the recently demonstrated requirement for B cells in the P. chabaudi-induced Th2 response [49], as these cells would be likely to generate high ligand density during antigen presentation. These views are somewhat at variance, however, with the recent findings that stronger T C R - M H C interaction favors a T h l response but weaker interaction favors a Th2 response in at least one model system [57]. The discrepancy may be partly explained by the earlier observation that the reciprocal dominance of ceU-mediated and humoral immunity shifts more than one time over a dose response of immunization [54]. Variables, such as route of administration, can also play a role in directing Th development, either by eliciting unique patterns of cytokines[58], inducing tolerance versus immunity [59], or perhaps through another, undefined mechanism. The form of the antigen, whether soluble (Thl-favoring) or particulate (Th2-favoring) [60], might also be an important influence in the type of response elicited by microbial stimuli. Although peptide antigens are considered the critical immunogens for driving specific T-cell responses, sugars and lipids may be equally important if they can make the necessary and sufficient 'adjustments' to the innate
milieu to direct biased Th development. Two molecules that stimulate monocytes/macrophages to make IL-12, and thus might augment T h l induction, have been identified. One of these, surprisingly, is the L. braziliensis homologue of elongation initiation factor 4A [61], while the other is the glycosylated lipid lipopolysaccharide. The observations that certain helminths, for example H. polygyrus, or particular helminth life-cycle stages, such as the schistosome egg, invariably induce Th2 responses has led to the suggestion that these organisms contain molecules that predispose the immune response to become Th2 like, perhaps by preferentially stimulating the production of IL-4 by one of the Th2-inducing populations discussed above. Pertinent to this point is the recent observation that a saccharide, lacto-N-fucopentaose III (LNFP-III), found on schistosome egg antigenic glycoproteins, directly induces IL-10 production in B cells [62]. By downregulating cytokine secretion by T h l cells, IL-10 could contribute to the overall Th2 dominance observed in immune responses to eggs. An additional unexpected facet to this story is the realization that T cells may also be capable of activation by atypical non-peptide epitopes. Recent description [63] of specificity for carbohydrate-modified peptides in the context of conventional class I restriction, a well characterized mycolic acid (lipid)-specific, CDl-restricted T-cell clone from a patient with tuberculosis [64 "°] and y8 T cells that recognize non-peptide antigens [65] provide increasing weight to the notion that our understanding of T-cell recognition during imnmne responses is not complete.
Conclusion The recent study of infectious disease models has provided insight into the requirements for developing Th2-type effector cells. Clearly IL-4 is a key cytokine for the induction of a Th2 response in many instances, but the source of IL-4 crucial for Th2 priming remains unclear in the majority of cases. There is considerable interest as to whether CD4 + NKI.1 + cells or similar pre-activated cells may be the elusive cellular source of early IL-4. The newly recognized potential for "non-conventional interactions between microbial ligands and immune cells has increased the excitement, albeit the complexity of the field. The finding that costimulation and other interactions that strengthen the response are virtually indispensable in promoting Th2 subset development holds promise for elucidating the molecular events that lead an uncommitted Th cell to differentiate in this manner.
Note added in proof Since the submission of this article, two more relevant papers have been published [66,67].
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Immunityto infection Acknowledgement The authors wish to thank many colleagues for helpful discussion and sharing of unpublished results. EJ Pearce is a recipient of a Burroughs Wellcome Fund New Investigator Award in Molecular Parasitology and National Institutes of Health AI32573. SL Reiner is a recipient of a Burroughs Wellcome Fund New Investigator Award in Molecular Parasitology and a Clinical Investigator Award from the National Institutes of Health (AI01309).
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EJ Pearce, Department of Microbiology, Immunology and Parasitology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853-6401, USA. E-mail:[email protected] SL Reiner, Gwen Knapp Center for Lupus and Immunology Research, Department of Medicine and Committee on Immunology, University of Chicago, 924 East 57th Street, Chicago, Illinois 60637-5420, USA. E-mail:[email protected] Author for correspondence: EJ Pearce.