The role of IL-10 in crossregulation of TH1 and TH2 responses

The role of IL-10 in crossregulationof TH1 and TH2 responses Tim R. Mosmann and Kevin W. Moore The identification of helper T (TH)-cellsubsets has greatly improved understanding of the regulation of immune effector functions. In addition to controlling humoral and delayed-type hypersensitivity responses, these subsets crossregulate by secreting mutually inhibitory cytokines. In this review, Tim Mosmann and Kevin Moore examine these phenomena and in particular the role of interleukin 1O, a cytokine secreted by TH2 cells that inhibits THl-cell function. The immune system can invoke many different effector mechanisms, with varying efficacy, against different types of infection. Antibodies are effective against soluble toxins and some types of bacteria, whereas cytotoxic T cells can kill virus-infected cells during an ongoing infection. The response pattern induced by a particular pathogen is usually predictable and often appropriate, but there are severe consequences if the incorrect pattern is induced. Recent information suggests that a major part of the regulation of effector function is carried out by T-cell subsets secreting defined patterns of cytokines that lead to strikingly different T-cell functions. Part of the regulation of immune effector functions may thus consist of the regulation of different T-cell subsets. Eukaryotic parasites are very sophistk:ated, and the immune system has considerable difficulty in removing them from the host. Possibly as a result, the immune response against many parasites is often very strong and sustained, and often appears to be locked in a particular regulatory state. Thus parasitology has provided some illuminating examples of different immune responses that have been very useful in vivo in showing the relevance of the types of T cell that will be discussed here. Cytokine synthesis patterns of mouse and human T cells Two very distinct cytokine secretion patterns were originally defined among a panel of mouse T-cell clones (Table 1) 1,2. TH1 , but not TH2, cells produce interleukin 2 (IL-2), gamma-interferon (IFN-~/) and lymphotoxin (LT), whereas TH2, but not T . I , cells express IL-4, IL-5, IL-6, IL-10 and an induced gene of unknown function, P600 (Refs 1-4). CD8 + T cells mainly produce the TH1cell cytokine pattern, although IL-2 synthesis is often low or absent s. The TH1- and TH2-cell patterns are welldefined and stable, at least in tissue culture. Evidence from strong immune responses, in both mice and humans, suggests that TH1- and TH2-cell patterns occur and are important in vivo (reviewed in Refs 6 and 7). Although many mouse T-cell clones fit either the TH1or the TH2-cell pattern, work from a number of laboratories has shown that other cytokine secretion patterns can readily be observed among mouse T-cell clones8-12. Such patterns include the TH0-cell pattern (Table 1), as well as other intermediate patterns that are most readily

Table 1. Cytokine secretion phenotypes of mouse T cells CTL

TH1

TH0

TH2

THp

IL-2 IFN-~/ LT

+/++ +

++ ++ ++

++ ++

-

++ -

GM-CSF TNF TY5 P500 H400 IL-3 Met-enkephalin

+ + ++ ++

++

+ + + + + ++ ++

-

+ +

++ ++ ++ ++ ++ ++ +

-

-

++ ++ ++ ++ ++

-

IL-4 IL-5 IL-6 P600 CSIF (IL-10)

++ ++ ++ ++

seen when unimmunized mice are used as donors of both stimulator and responder cells for T-cell cloning8. These results fit well with the data obtained with many human T-cell clones 13-16. Cytokine production by normal mouse spleen T cells, especially from unimmunized mice, shows that many normal T cells, when first stimulated, produce large amounts of IL-2 but not other T-ceU cytokines s,17,18. Thus the resting T cell that has not recently been stimulated may produce only IL-2 on first contact with antigen, and the T cells producing multiple cytokines may represent later, more differentiated phenotypes. This model (Fig. 1) is supported by the results of stimulation of normal cells in vitro, since both mouse 17 and human 19 cells produce mainly IL-2 when first stimulated, and acquire the ability to produce cytokines such as IL-4 and IFN-~/ a few days after they are stimulated in tissue culture. Similar results have been obtained in vivo (Ref. 8 and N.F. Street and T.R. Mosmann, unpublished), especially when strong immunogens are used. These experiments provide strong support for the hypothesis that the differentiation from IL-2-producer (THP) to TH0, TH1 and TH2 cells occurs in vivo. The proposed relationships among the various cytokine secretion phenotypes are

© 1991, ElsevierSciencePublishers Ltd, UK. 0167--4919/91/$02.00

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-

-

Fig. 1. Cytokine secretion phenotypes of helper T (CD4 +) cells. The proposed relationships among the various cytokine secretion phenotypes are shown by dotted arrows since there is no clear evidence for the pathways involved.

shown in Fig. i but as yet there is no clear evidence for the pathways involved. One of the most important questions is whether Tiql, T.2 and other phenotypes can differentiate from a single Tiqp cell after activation, or whether the THp cells are already committed to a particular cytokine pattern before exposure to antigen. Selective activation and differentiation of T-cell subsets The regulation of T-cell differentiation into various cytokine secretion phenotypes is not well understood. It is important to distinguish signals that induce the differentiation of T-cell subsets from signals that induce suppression or enhancement of the growth and function of cells that have already differentiated into TH1, TH2 or other phenotypes. The cytokine environment that is present during differentiation may be an important influence on the type of TH cell that will be generated. Gajewski et al. 2° have shown that TH1 cells are preferentially obtained when CD4 + cells are cloned in the presence of IFN-y. Conversely, the presence of IL-4 during TH-cell effector generation in vitro enhances the development of IL-4/IL-5-secreting effectors while suppressing the development of effectors that can secrete IL-2 and IFN-y (S. Swain, pers. commun.). Both of these effects may be attributable to differentiative events, although influences on selective outgrowth have not been formally excluded. It is also likely that antigen-presenting cells (APCs) regulate the differentiation of TI-I cells, since different APCs can preferentially present different classes of antigen.

Both cytokines and APCs also influence the growth or activation of the 'mature' TI-I1 and TH2 phenotypes. IFN-7 inhibits the proliferation of TH2 cells responding to either IL-2 or IL-4. IFN-y does not inhibit TH1 cells9m. IL-10 inhibits the synthesis of cytokines by Ttql cells and, although growth factor responsiveness is not affected, IL-10-induced reduction in IL-2 synthesis can result in decreased proliferation22. APCs in liver present antigen to Ttal but not to Tiq2 cells22; this may be related to the ability of macrophages to present antigen preferentially to T,1 cells23. Given the importance of the regulation of the class of immunity induced against a particular pathogen, it is likely that the full regulation of TH-cell differentiation, activation and proliferation will involve all of these and other mechanisms. Cell surface markers Several studies have correlated cell surface markers with cytokine secretion phenotypes24-27. Some markers, such as CD44 and the CD45 isoforms, appear to be related to the activation state rather than to the cytokine secretion pattern of the cell. Since the number of cytokine secretion phenotypes is likely to be large, they will probably need to be defined by multiple cell surface markers27. Functions of T-cell subsets B-cell help can be mediated by both TH1 and TH2 clones, but TH2 cells appear to be much more efficient2s-31. TH1 cells do not help B-cell antibody secretion

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in some circumstances; this may be due to an imbalance of THl-cell cytokines29, or to the ability of TH1 cells to kill B cells, probably via IFN-y and LT production. IL-4 (from TH2 cells) selectively induces immunoglobulin (Ig) gene switching to the e and the yl loci, whereas IFN-'y (from TH1 cells) inhibits IL-4-induced switching, and induces switching to ~2a 32-34. The cytokines secreted by the TH cells appear to be more important for the outcome than the cell-mediated signals, since either TH1 or TH2 cells can provide help for IgE production in the presence of IL-4 and in the absence of IFN-y 29,36. TH2-cell-like responses in vivo (high IL-4 and IL-5 production) are associated with high antibody levels, whereas THl-cell-like responses (high IFN-~ production) may show antibody production but in extreme cases are associated with vrrong delayed-type hypersensitivity (DTH) and suppressed antibody responses. In addition to enhancing IgE production via IL-4, TH2 cells also enhance two other features of allergic responses. First, IL-3 and IL4 are mast cell growth factors that act in synergy, at least in vitro 37, and second, IL-5 induces the proliferation and differentiation of eosinophils both in vitro and in vivo 38,39. Thus TH2-cell activation increases not only the level of IgE synthesized, but also potentially increases ~he number of cells that can bind IgE and use it as an antigen receptor for subsequent activation. TH 1 cells can mediate a DTH reaction when injected with antigen into the footpads of mice4°. This reaction involves IFN-'y and shows rnainly granulocyte infiltration with edema due to vascular leakage 41. These features are more similar to the Jones-Mote than to the tuberculintype DTH reaction, which mainly involves monocyte infiltration. It is not known which type of cell mediates the latter reaction but it may be a combination of TH1 and TH2 cells, or some other cell type, alone or in combination with TH1 cells. Because of the recruitment and activation of cells suc]h as granulocytes and macrophages to the site of infection, DTH can be very effective against local infections, and especially against intracellular parasites. Several other THl-cell functions also have the effect of enhancing the destruction of infected cells (reviewed in Ref. 6). Thus TH1 cells may deal more effectively with intracellular pathogens, whereas TH2 cells, by inducing strong antibody responses, may be more important for dealing with extracellular organisms and their secreted products, as suggested by Janeway and colleagues 42. The functions of other TH-cell types, such as the TH0 and THp, are less well understood, although some speculations can be made, based on their cytokine production. For example, the cells producing IL-2, IL-4 and IL-5 but not IFN-y may be excellent helper cells for B-cell antibody synthesis, since they secrete cytokines that strongly stimulate B cells without IFN-y which partially inhibits the B cells. The THp cells that secrete only IL-2 when first stimulated may function to expand the population of antigen-specific cells, before the development of more potent effector phenotypes after such proliferation. Mixtures of cell types may result in complex functions, since it may not be possible to predict the effector functions of mixtures of cell types from the functions of individual cells.

Crossregulation of T cells During many strong immune responses, antibody production and DTH responses are mutually exclusive43. Since TH2 and TH1 cells appear to be at least partially responsible for antibody and DTH responses respectively, it is possible that the reciprocal relationship between these two responses is that TH1 and TH2 cells are mutually inhibitory and/or self-stimulatory. Two actions of cytokines are consistent with this: IFN-~/inhibits the growth of TH2 cells9,21and IL-4 preferentially stimulates growth of TH2 cells21,44. Since there is clear evidence for the inhibition of DTH responses during strong antibody responses, a crossregulatory activity that was produced by Tiq2 cells and inhibited the growth or function of TH1 cells was searched for. A previously unknown cytokine that suppressed the production of cytokines by TH1 cells responding to antigen plus APCs was found3. Interleukin 10 (IL-10) (originally known as cytokine synthesis inhibitory factor (CSIF)) is an acid-labile 3540 kDa homodimer that is produced by TH2, but not TH1, cells and acts to inhibit synthesis of most or all cytokines by TH1 but not TH2 cells. Inhibition of cytokine synthesis, especially of IFN-y, by IL-10 can be greater than 90% but complete inhibition is not obtained. This may be due to the kinetics of action - IL-10 shows little or no inhibition of cytokine production before about 8 h, and then inhibits synthesis very effectively from this time onward. Cytokines, such as IFN-y, that are synthesized over a prolonged period are thus inhibited to a greater extent than cytokines synthesized within the first 8 h after stimulation. In contrast to its ability to inhibit cytokine synthesis, IL-10 does not affect the antigen-stimulated proliferation of TH 1 clones, provided that exogenous IL-2 is supplied 3. Several features of the action of IL-10 suggest that it may act indirectly to cause a reduction in THl-cell cytokine synthesis. In addition to the delay in onset of inhibitory activity, IL-10 can inhibit the synthesis of cytokines by TH1 cells that respond to antigen plus APCs, or anti-CD3 antibody plus APCs. In contrast, IL-10 does not affect cytokine synthesis in response to the equally strong stimuli of Concanavalin A (ConA) or anti-CD3 antibody bound to a plastic surface. Since IL-10 acts only when APCs are present, it was suggested 3 that it may act via the APC by inhibiting antigen presentation or the production of a costimulatory signal required by the T cells. The delayed onset of IL-10 action and the effects of changing the assay parameters are also consistent with indirect action. Since IL-10 inhibits the synthesis of cytokines by TH1 cells and cytotoxic T lymphocyte (CTL) clones synthesize the THl-cell pattern of cytokiness, the effect of IL- 10 on CTL clones was also tested. As with T H1 clones, cytokine synthesis of CTL clones was inhibited but proliferation was not affected (T.A.T. Fong, D.F. Fiorentino and T.R. Mosmann, unpublished). Thus IL-10 inhibits synthesis of the THl-cell pattern of cytokines by both of the cell types that express this pattern. IL-10 cDNA clones and anti-IL-10 monoclonal antibodies When it became apparent that CSIF activity was not mediated by a known cytokine, an IL-10 cDNA clone

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was isolated from an induced TH2-cell library using the pcD-SRa cloning vector that allows high expression of functional protein in COS cells4s. The cDNA clone has an open reading flame of 178 amino acids and the first 18 residues appear to be a hydrophobic leader sequence characteristic of a secreted protein. Two potential N-linked carbohydrate attachment sites are present, and studies with tunicamycin and glycosidase suggest that one of these sites is glycosylated only on some IL-10 molecules4s, which accounts for the heterogeneity of monomer molecular masses (20 kDa and 16 kDa). IL-10 is encoded by a single-copy gene, with at least four exons. IL-10 is synthesized by T.2, but not TH1 or CTL, clones and also by mast cell lines, Ly-1 B-cell tumour lines and normal Ly-1 B cells45,46. Since this represents a novel mouse gene with multiple activities in the immune system, the name IL-10 was proposed4s. Six monoclonal antibodies (mAbs) that are specific for IL-10 have been isolated, of which four, all IgM, blocked biological activity. The recognition of separate epitopes by two mAbs, SXC1 and SXC2, allowed the establishment of a sensitive ELISA for IL-10 (Ref. 47). Since any of these four mAbs can deplete more than 95% of the IL-10 activity from TH2-cell supernatants, it appears that IL-10 (as defined by the cDNA clone) accounts for most, or all, of the CSIF bioactivity produced by TH2 cells. Human IL-10 cDNA clones Human IL-10 (hIL-10) cDNAs were isolated from an induced human T-cell cDNA library by crosshybridization with an mlL-10 probe48. A single 18 kDa hlL-10 polypeptide that lacked significant N-linked carbohydrate was expressed in transfected COS7 cells. Recombinant hlL-10 inhibits cytokine synthesis by mouse cells as well as by human peripheral blood mononuclear cells (PBMCs) stimulated with phytohemagglutinin (PHA) or anti-CD3 antibodies48. For mlL-10 (Ref. 3) parallel results have been observed at the RNA level: hlL-10 reduces the level of IFN-~/mRNA that can be detected in stimulated human PBMC cultures 48. mlL-10 is not active on human cells. Homology of IL-10 to an Epstein-Barr virus gene raiL-10 and hIL-10 sequences contain no significant homology to known cytokines or growth factors but show striking homology to a previously uncharacterized open reading frame in the Epstein-Barr virus (EBV), BCRF1 (Refs 45,48,49). The homology to BCRF1 is confined to the mature protein coding sequence and is not detected in the signal sequence or 5'- and 3'untranslated regions, where the raiL-10 and hlL-10 genes are highly related. At the amino acid sequence level, hlL-10 and BCRF1 are the more closely related (approximately 84%), while at the DNA sequence level, mlL-10 and hlL-10 are more closely related (approximately 81%). We tentatively conclude that BCRF1 represents a captured, processed cellular IL-10 gene and that the viral protein is constrained by selective pressure to resemble the human cytokine. The BCRF1 protein has been expressed from a polymerase chain reaction (PCR)-amplified gene segments°. Like hlL-10, the BCRF1 protein inhibits IFN-~ synthesis by both mouse T cells and human PBMCs stimulated by

lectin or IL-2 (Ref. 50). Since natural killer (NK) cells are the principal source of IFN-~/ in IL-2-stimulated PBMCs51,52, it appears that the BCRF1 product and hiE-10 (D.H. Hsu, K.W. Moore and H. Spits, unpublished) can inhibit cytokine synthesis, not only by T cells, but also by NK cells. The observation that the viral protein has functional cytokine activity suggests that it probably plays a role in the interaction of virally-infected cells with the immune system. IFN-~/inhibits the early stages of generation and outgrowth of EBV-infected B cells in vitro 53-55. BCRF1 transcription is detected during the late phase of the lytic virus cycle56, and BCRF1 may, therefore, play a role in defending infected cells during the productive stage of virus infection67,58. A similar strategy may be used by certain poxviruses, whose genomes contain a homologue of the mammalian receptor for tumour necrosis factor (TNF) 59. IL-10 in parasite infections During Nippostrongylus brasiliensis infections, mice mount a strong TH2-cell-like response, including the ability to synthesize more IL-4 and IL-5 and less IFN-~/ and IL-2 (N.F. Street and T.R. Mosmann, unpublished) and a greatly increased quantity of IL-10 (T.R. Mosmann, unpublished). IL-10 produced in response to lectin appears to cause the decrease in IFN-~t synthesis, since the addition of anti-IL-10 mAb increases 1FN-~t synthesis above control levels (T.R. Mosmann, unpublished). During Schistosoma mansoni infections, mice mount a strong TH2-cell-like response only after egg laying begins. At that time, cells from infected mice produce substantial amounts of IL-10 in response to antigen, but no detectable IFN-~/(A. Sher and T.R. Mosmann, unpublished). However, in the presence of anti-IL-10 mAb, significant levels of IFN-~ are synthesized in response to antigen. Thus IL-10 is a major mediator of the suppression of THl-cell-like functions seen in vitro with cells from mice infected with these two parasites. Conclusion The crossregulation of antibody and DTH responses may be at least partially explained by mutual inhibition of TH1 and TH2 cells. Some of the mediators have now been identified: IFN-~ inhibits TH2-, but not THl-cell proliferation, whereas IL-10 inhibits the synthesis of cytokines by TH1 but not TH2 cells. Since several intermediate cytokine secretion phenotypes exist, further work will be needed to resolve the cytokine regulation of each population. The cross-inhibitory nature of TH1- and Tr~2-cell responses and the sustained responses that can be induced by parasite infections raise the question of how the system returns to a state of balance after a strong TH1- or TH2-cell response. It has previously been suggested 6 that antibody subclasses may play a regulatory role in restoring the equilibrium. It is also possible that TH1, TH2 and other cells that secrete high levels of cytokines are shortlived differentiation states, and that they die or change phenotype after the antigen stimulus is removed. What is the advantage of the locking mechanism that maintains the immune response in either the TH1 or TH2

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state during strong responses? This is especially puzzling since this lock can be very deleterious if the wrong choice is made, for example in the response to Leishmania infection in BALB/c mice and some humans. Future experiments may reveal why strong antibody and DTH responses are mutually exclusive rather than coexistent. Tim Mosmann is at the Dept of Immunology, Room 865 Medical Sciences Building, University of Alberta, Edmonton, Alberta T6G 2H7, Canada and Kevin Moore is at the Dept of Immunology, D N A X Research Institute for Cellular and Molecular Biology, 901 California Avenue, Palo Alto, CA 94304, USA.

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