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Interleukin 1 and T-cell activation
Imn'unology Today, vol. 8, No. 11, 1987
6 Sondel, P.M., Hank, J.A. etal. (1986) J. Immunol. 137, 502 7 Vandenbank,A.A. Offrer, H., Reshef,T. etal. (1985) J. Immunol. 135, 229 8 Hohlfeld, R., Tokya, K.V., Heininger, K., Gross-Wilde, H. and Kalies, I. (1984)Nature 3i0, 244 9 Holmdahl, R., Klareskog,L., Rubin, K., Larsson,E. and Wigzell, H. (1985) Scand. J. Immunol. 22,295 10 Champion, 8.R.,Varey,A.M., Katz, D., Cooke, A. and Roitt, I.M. (1985) Immunology 54, 513 11 Cooke, A., Hutchings,P.R.and Playfair,J.H.L.(1987)Nature 273, 154 12 Naysmith,J.D., Ortega-Pierres,M.G. and Eison,C.J.(1981) Immunol. Rev. 55, 41 13 Moore, J.S.and Calkins,C.E. (1985) J. Immunol. 134, 3838 14 Watt, G.J., Elson,C.J., Healey, D.G., Oryan, A. and Hooper, D.C. (1986) Eur. J. Immunol. 16, 1131 15 Culbert, E.J.,Watt, G.J., Riddell, P.E.,Hill, C.J.and Elson,C.J. (1986) in Immune Regulation by Characterized Polype.ptide= (UCLA Syrup. Mol. Cell. Biol., New Ser. Vol. 41) (Goldstein, G., Buch, J.F.and Wigzell, H., eds), P!an R. Liss,Inc. 16 Playfair,J.H.L.and Marshall-Clarke,S. (1973) Nature (New Biol.) 243, 213 17 Cox, K.O. and Keast, D. (1973)Immunology25, 531 18 Cox, K.O. and Keast, D. (1974) Clin. Exp. Immunol. 17, 319 19 Hooper, D.C., Young, Ji., Elson,CJ. and Taylor, R.B.(1987) Cell. Immunol. 106, 53 20 Hooper, D.C. and Taylor, R.B.(1987)Eur. J. Immunol. 17, 797 21 Parish,C.R. (1972) Eur. J. Immunol. 2, 143 I wish to thank C.J. Elson, R.B.Taylorand J.L. Young for critical 22 Kappler,J.W. and Marrack, P.C.(1976) Nature 262, 797 review of this manuscript. 23 Schwartz,P.H. (1985) Annu. Rev. Imrnunol. 3, 237 24 Eichmann, K., Falk,I., Melchers, I. and Simon, M.M. (1980) J. Exp. Med. 152,477 Refel~ces 25 Battisto, J.R.and Ponzio, N.M. (1981)Prog. Allergy28, 160 1 Bumet, F.M (1959) The Clonal Selection Theory of Acquired 26 Jenkins,M.K. and Schwartz,R.H. (1987) J. Exp. Med. 165, Immunity, CambridgeUniversityPress 302 2 Elson,CJ., Naysmith,D.G. and Taylor, R.B.(1979)Int. Rev. 27 Lamb,J.R., Skidmore, B.J.,Green, N., Chiller, J.M. and Exp. Path. 19, 137 3 Karray,S., Lymberi, P., Avrameas,S. and Coutinho, A. (1986) Feldmann, M. (1983)J. Exp. Med. 157, 1434 28 Gammon, G., Dunn, K., Shastri, N. etal. (1986)Nature 319, Stand. J. Immunol. 23,475 413 4 Cohen, I.R.,Gioberson,A. and Feldman,M. (1971)J. Exp. 29 Kappler,J.W., Roehm, N. and Marrack, P. (1987) Ce1149, Med. 133.834 273 5 Cohen. I.R.and Wekerle, H. (1973)./. EXP. Med. 137. 224
]
¢~:lusi~s
The results I have discussed show that T helper cells which recognize autologous RBC and are likely to be involved in autoimmunity exist in the normal animal. Reports from other investigators 71° support this contention. How could such cells escape deletion? It is probably not the result of an age-related decline in the efficiency of a deletion mechanism, as T cells from three-week old mice react strongly against MRBC (approximately 60% of the response given by nine-week old animals; D.C. Hooper, unpublished). By comparison, the appearance of T cells reactive against self ia antigens in adult mice appears to be a function of advancing age2s. It is unlikely that culture reactivates T cells which have been rendered anergic in vivo because T-cell clones inactivated in vitro remain so beyond the duration of the primary reaction 26. However, clonal deletion/inactivation of T cells definitely occur26-29. I suggest that this may happen with T helper cells specific for self antigens which are constitutively expressed on la-bearing cells or which can be presented in a nonimmunogenic fashion on such cells (for example, by not stimulating interleukin 1 production). I suggest, however, that T helper cells specific for self antigens which must be processed and presented to be recognized in context wi~h self la are not deleted.
i I i t
Interleukin I and T-cell adivation More than eight years have passed since the historic Second International Lymphokine Workshop in Ermatingen, Switzerland, where S. Gillis, J. Farrar, S. Mizel, V. Paetkau, K. Smith, J. Watson and D. Wood collectively gave birth to the concept of the 'interleukins'. This concept would provide the field of lymphokines with a firm foundation upon which to move from phenomenoIogy to a more refined understanding of important immunomodulators. During the past few years, the record of accomplisi,ments has been outstanding: interleuk,•s 1 and 2 have been purified, cDNAs cloned and expressed, receptors characterized and in the case of 11.-2, also cloned. We have applied our detailed understanding of the immunobiology of 11.-2 to problems in T-cell tumor biology as well as to the events that follow infection of T cells with the human immunodeficiency virus. Although the cloning of murine and human interleukin 1 (IL-1) cDNAs 1-3 has revealed the basic stru~ure ~ t ~ r ~ t University ~ r f m, ~ =. , , .n. , Lf vn{. ,=..,~vs.,.v,v~j, A,f;rrnh;n!..~'q~.,~,,.w =n,qt . . . . n,~lnnu W=~,=..... Medical Center, Winston-Salem,NC 27103, USA.
~-~.
330
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Stem B. Mizel of IL-1, as well as the existence of an IL-1 gene family, we still have no definitive picture of its role in T-cell activation. Is IL-1 an essential signal in T-cell activation or does it enhance responses triggered by specific cell surface interactions between antigen-presenting cells and T cells? What is the nature of the active species of IL-1 in T-cell activation - is it the well-characterized ~ow molecular weight form found in the culture medium of stimulated IL-l-producing cells, or a membraneassociated species? How is IL-1 production initiated during an immune response? Does the antigen- or mitogen-induced physical coupiing of T cells and accessory cells (macrophages or dendritic cells) provide a signal for the induction of IL-1 synthesis? Or do T cells release a soluble mediator that is ultimately responsible for triggering IL-1 production? Are resting T cells IL-1 responsive or do they acquire responsiveness (IL-1 receptors) after exposure to antigen or mitogen in the presence of accessory cells?
m J
© 1987. Elsevier Publications. Cambr!~ge
0 1 6 7 - 4919/871502.00
eon n en?ar -
Immunology Today, vol. 8, No. 11, 1987
On the basis of earlier results4, it was assumed that the sole task of II.-1 was to provide an essential signal which in conjunction with antigen or mitogen could trigger T-cell IL-2 production as well as IL-2 receptor expression two critical events in the pathway leading to T-cell proliferation. However, the picture today does not look so simple. For example, it remains unclear whether IL-1 is absolutely required to initiate T-cell activation. Instead of analysing the action of endogenously produced IL-1 in unfractionated cultures of lymphocytes, earlier studies focused exclusively on the effect of exogenous IL-1 in accessory cell-depleted cultures. These experiments did not show that IL-1 was essential in T-cell activation, but rather that IL-1 could reconstitute responses in the presence of limiting numbers of accessory cells. With the availability of neutralizing antibodies against murine I L - 1 , it has finally been possible to assess the contribution of endogenously produced IL-1 in T-cell activation in cultures of unfractionated lymphocytesS. The results are quite clear: anti-lL-I antibodies have no effect on T-cell proliferation induced by antigen (soluble or alloantigen) or mitogen in unfractionated populations of spleen or lymph node cells. These results are consistent with an enhancing role - as opposed to an obligatory role - for IL-1 in T-cell activation. The recent work from Koide etal. 6 supports the notion that IL-1 has a limited ability to activate T cells in the, absence of accessory cells. Using purified murine T cells at different stages of activation, II.-1 had no detectable effect on T-cell proliferation in the presence or absence of mitogens or antigens. As in earlier investigations, however, IL-1 did augment proliferation in the presence of low numbers of accessory cells, in this case, splenic dendritic cells. In the presence of optimal numbers of accessory cells, T-cell activation may be solely dependent upon a critical level of surface receptor interactions between T cells and a c c e s s o r y t-~lle i ^ proc~sed a.ug~,~c~5 ii ..... i# ~.... .. ... .. . o,,,F,,=, major histocompatibility complex (MHC) antigen and the T-cell receptor, Ly 1, L3T4 and LFA antigens). At low concentrations of accessory cells, although the number of interactions may be insufficient to trigger T-cell activation, they can act in concert with IL-1 to produce a response equivalent to that obtained with an optimal concentration of antigen-presenting accessory cells. Koide et al. 6 have made the novel suggestion that the enhancing effect of IL-1 on T-cell activation is not the result of a direct action on T cells, but instead results from stimulation of dendritic cells. This intriguing possibility deserves additional attention. Nonetheless, it is difficult to dismiss the T cell as a direct recipient of IL-I action. T cells bear high-affinity IL-1 receptors 2 and exhibit a number of metabolic responses to IL-!. For example, it has recently been shown 8 that JL-1 ac-ts in concert with phytohemagglutinin (PHA) to enhance markedly the transcription of the genes for IL-2, IL-3, the IL-2 receptor, Ly-1, transforming growth factor-13 and c-rnyc in the murine T-cell lymphoma, LBRM33-1A5. By itself, IL-1 had little if any stimulatory effect. Thus, the enhancing action of II.-1 on gene transcription is consistent with the concept of IL-1 as an enhancing factor for T-cell activation. How iL-! synthesis is induced during an immune response has also been a subject of intense study for more than a decade. A number of studies 4 indicate that T cells can induce macrophage IL-1 production in the -.'-:---
'-'---
presence of antigen or mitogens such as PHA or concanavalin A (Con A). However, a recent study by Koide and Steinrnan 9 is clearly at odds with these earlier observations. These investigators reported that lipopolysaccharide (LPS), but not tetradecanoyl phorbol 13acetate (TPA), gamma interferon, Con Ao colonystimulating factor, IL-3, tumor necrosis factor, or activated T cells could induce IL-1 gene transcription by murine macrophages. At this time, it is not possible to reconcile the results of Koide and Steinman w;th those of other investigators. I find it difficult to imagine how IL-1 is produced during immune responses if not as a result of interactions between accessory cells and T cells. The studies of Mizel et al. lo and Farr et al. il suggested that contact between accessory cells and T cells was a prerequisite for the induction of IL-1. However, two recent studies 12.13 indicate that T cells can activate IL-1 production by either cell contact or the release of a lymphokine that appears to be distinct from IL-2, gamma interferon, B-cell stimulatory factor- 1, colony-stimulatory factor-1 or tumor necrosis factor. The antigen- or mitogen-mediated coupling of T cells and accessory cells an interaction involving a complex of processed antigen, class II histocompatibility antigen and T-cell receptor may provide the intttial stimulatory signal for IL-1 production. Subsequently, activated T cells may release a lymphokine that can further up-regulate IL-1 synthesis and secretion. In 1985,~ Kurt-Jones et al. 14 identified a novel, membrane-a~sociated form of IL-1. Subsequently, a similar type! of activity was detected using paraformaldehyde-fixed tumor B cells, dendritic cells and fibroblasts, when stimulated cells were tested for bioactivity in one or more IL-1 bioassays. Conlon eta/. Is have argued that IL-I(~ rather than IL-113 is the membrane-associated form of IL-1. Although the concept of a surface membrane form of IL-1 is exciting, a note of caution is warranted. Using iodination with lactoperoxidase, it has not been possible to detect a cell surface form of IL-1 on stimulated rnacrophages (S. Mizel, unpublished). In addition, immunoprecipitation analysis of 35S-methionine-labeled macrophages has failed to detect a membrane-associated form of IL-1 at times when parallel cultures of paraformaldehyde-fixed cells exhibit bioactivity in I!.-1 assays(L. Minnich, J. Suttles and S. Mizel, unpublished). Leakage of IL-1 from fixed cells could account for the observed 'membrane IL-I' activity. Clearly, more detailed biochemical studies are required to provide a definitive statement on the question of membrane-associated IL-1. Although gaps remain in our knowledge of the function of IL-1 in T-cell activation, I offer the following working model. In tha presence of a specific antigen or T-cell mitogen, T cells and accessory cells are mutually stimulatory. The accessory cell is induced to begin IL-1 synthesis and secretion. In return, the T-cell initiates IL-2 and IL-2 receptor synthesis and expression. In addition, T cells are stimulated to produce IL-1 receptors and thus become fully responsive to IL-1. This conclusion is based upon the recent demonstration of up-regulation of IL-1 receptors on T cells incubated with stimulant and accessory cells16, IL-1 responsiveness confers upon the T cell a ......y. .to heightened o"~':~'~ . . ~,,-..,,,,,,-,"~.... I1.=1_ " "~ and IL-2 receptors ia response to processed antigen/class II MHC antigen or mitogen. Interaction between IL-2 and its receptor then results in T-cell proliferation. Activated T cells may also
331
Immunology Today, vol. 8, No. 11, 1987
J produce a lymphokine that augments the ability of accessory cells to produce IL-1, thus providing for a secondary amplification loop in the interactions between accessory cells and T cells. When this model is put to the test, IL-1 could well provide some interesting surprises. 1 Lomedico,P.i., Gubler, U., Hellmaluh C.P.etaL (1984) Nature 312, 458-462 2 Auron. P.E.,Webb, A.C., Rosenwasser,L.J.etal. (1984)Proc NatlAcad. Sci. USA 81, 7907-7911 3 March, CJ., Mosley, B., Larsen,A. etal. (1985) Nature 315, 641-647 4 Mizel, S. (1982)Immunol. Rev. 63, 51-72 $ Mizei, S. in New Horizons in Therapeutics. Cellular and Molecular Aspects oflnflamrnation (Poste,G. and Crooke, S.T., ~:ls), PlenumPress(in press) f~ Koide, S.L, Inaba, K. and Steinman,R.M.(1987)J. Exp. Me
7 Dower, S.K., Kronheim, S.R.,March, C.J. etal. (1985)J. Exp. Med. 162, 501-515 8 Hagiwara, H., Huang. H.S.,Arai, N. etal. (1987)./. lmmunoL 138, 2514-2519 9 Koide, S. and Steinman, R.M.(1987)Proc. NatlAcad. SCL USA 84, 3802-3806 10 Mizel, S.B.,Oppenheim,J'J. and Rosenstreich,D.L. (1978) J. Immunol. 120, 1497-1503 11 Farr,A.G., Dorf, M.E. and Unanue, E.R.(1977)Proc. Natl Acad. Sci. USA 74, 3542-3546 12 Weaver, C.T. and Unanue, E.R.(1986)J. Immunol. 137, 3868-3873 13 Takacs,L., Berzofsky,J.A., York-Jolley,J. etal. (1987) J. ImmunoL 138, 2124-2131 14 Kurt-Jones,E.A., Belier, D.I., Mizel, S.B.and Unanue, E.R. (1985) Proc. NatlAcad. Sci. USA 82, 1204-1208 15 Conlon, P.J.,Grabstein, K.H., Alpert, A. etaL (1987) J. Immunol. 139, 98-102 16 Shirakawa,F., Tanaka,Y., Ota, T. etal. (1987) J. Immunol. 138. 4243-4248
s cataractformation an autoimmune phenomenon? The hypothesis that cataractogenesis is an autoimmune phenomenon is not a new one - it was suggested by Woods and Burky 1 as long ago as 1927. Recently, however, I. Angunawela at the University of Peradeniya in Sri Lanka has reopened the debate on cataract formation by reporting a significant increase in the incidence of antibody directed against lens antigens in the serum of patients with cataractous lenses and in the serum of diabetic patients2. In addition, immunoglobulin deposits could be detected on the celis of cataractous lenses removed from nondiabetic and diabetic I=atients. The close relationship betweer, diabetes and senile cataracts is a iong-standing clinical observation that takes on greater meaning in light of these recent findings. But interpreting the presence of lens-specific antibodies in the serum of catara~ous patients should be considered with caution, since similar antibodies have b~!en demonstrated in approximately 5(Ho of the norma'~ individuals tested 3.4. It is quite possible that an increased incidence of antibody directed against the lens in cataractous patients is the result of cataractogenesis and not the cause. Nonetheless, Angunawela's recent paper resurrects some interesting questions regarding the immunobiology of the lens. The notion that components of the lens are potc-ntial autoantigens was suggested more than 80 years ago by Uhlenhuth s, who demonstrated that serum ~r,~mrabbits immunized with bovine lens extracts reacted- ,~,~':,lens proteins from a wide variety of vertebrate species. Two decades later, Verhoeff and Lemoine6 suggested that such immune factors might be related to the persistent ocular inflammatory diseases that occasionally follow penetrating injury to the lens. Indeed, it has been suggested that the crystallin proteins of the lens are sequestered from the immune system early in embryonic
332
Department of Ophthalmology, Universi~ of Texas Health Science Centerat Dallas, Dallas, TX 75235, USA.
JmyY. Niedeom development and thus do not induce immunological tolerance 7. Not only are the cells of the lens isolated from systemic circulation by a collagenous capsule inaccessible to blood vessels, but the lens and its capsule reside within an immunologically privileged compartment- the anterior chamber of the eye. The early sequestration of the lens during ontogeny implies that, if released into the peripheral circulation, crystallins could act as autoimmunogens in the adult. Although homologous lens proteins can elicit antibody synthesis8, attempts to demonstrate T cell-mediated immune responses to homologous lens antigens in experimental animals have been unsuccessful 9. It has been suggested that apparent T-cell tolerance to homologous crystallins may be an active process primed by exposure to low doses of homologous antigen 9. This hypothesis is supported by reports that oLand ~ crystallins can be readily detected in the aqueous humor of normal individuals 1°. Leakage of antigens from the lens into the systemic circulation may occur often enough to explain the presence of serum antibody against crystallins in approximately 50% of the normal population 3.4. Thus, it is possible that autoantigens in the lens are prevented from eliciting severe autoimmune disease by a process of active tolerance. The presence of lens-specific antibodies in many normal individuals and the appearance of crystallins in the aqueous humor of these individuals are intriguing in light of recent findings relating to the immunological privilege within the anterior chamber of the eye. It has been recognized for over a century that foreign tissue grafts can escape immunologic rejection and reside for prolonged periods within this environment 11. This 'immunological privilege' was orginally attributed to the sequestration of the graft within an anatomical compartment uniquely devoid of lymphatic drainage channels and thus (~ 1987, Elsevier Publications, Cambridge 0167 - 4919/87/$02.00
6 Sondel, P.M., Hank, J.A. etal. (1986) J. Immunol. 137, 502 7 Vandenbank,A.A. Offrer, H., Reshef,T. etal. (1985) J. Immunol. 135, 229 8 Hohlfeld, R., Tokya, K.V., Heininger, K., Gross-Wilde, H. and Kalies, I. (1984)Nature 3i0, 244 9 Holmdahl, R., Klareskog,L., Rubin, K., Larsson,E. and Wigzell, H. (1985) Scand. J. Immunol. 22,295 10 Champion, 8.R.,Varey,A.M., Katz, D., Cooke, A. and Roitt, I.M. (1985) Immunology 54, 513 11 Cooke, A., Hutchings,P.R.and Playfair,J.H.L.(1987)Nature 273, 154 12 Naysmith,J.D., Ortega-Pierres,M.G. and Eison,C.J.(1981) Immunol. Rev. 55, 41 13 Moore, J.S.and Calkins,C.E. (1985) J. Immunol. 134, 3838 14 Watt, G.J., Elson,C.J., Healey, D.G., Oryan, A. and Hooper, D.C. (1986) Eur. J. Immunol. 16, 1131 15 Culbert, E.J.,Watt, G.J., Riddell, P.E.,Hill, C.J.and Elson,C.J. (1986) in Immune Regulation by Characterized Polype.ptide= (UCLA Syrup. Mol. Cell. Biol., New Ser. Vol. 41) (Goldstein, G., Buch, J.F.and Wigzell, H., eds), P!an R. Liss,Inc. 16 Playfair,J.H.L.and Marshall-Clarke,S. (1973) Nature (New Biol.) 243, 213 17 Cox, K.O. and Keast, D. (1973)Immunology25, 531 18 Cox, K.O. and Keast, D. (1974) Clin. Exp. Immunol. 17, 319 19 Hooper, D.C., Young, Ji., Elson,CJ. and Taylor, R.B.(1987) Cell. Immunol. 106, 53 20 Hooper, D.C. and Taylor, R.B.(1987)Eur. J. Immunol. 17, 797 21 Parish,C.R. (1972) Eur. J. Immunol. 2, 143 I wish to thank C.J. Elson, R.B.Taylorand J.L. Young for critical 22 Kappler,J.W. and Marrack, P.C.(1976) Nature 262, 797 review of this manuscript. 23 Schwartz,P.H. (1985) Annu. Rev. Imrnunol. 3, 237 24 Eichmann, K., Falk,I., Melchers, I. and Simon, M.M. (1980) J. Exp. Med. 152,477 Refel~ces 25 Battisto, J.R.and Ponzio, N.M. (1981)Prog. Allergy28, 160 1 Bumet, F.M (1959) The Clonal Selection Theory of Acquired 26 Jenkins,M.K. and Schwartz,R.H. (1987) J. Exp. Med. 165, Immunity, CambridgeUniversityPress 302 2 Elson,CJ., Naysmith,D.G. and Taylor, R.B.(1979)Int. Rev. 27 Lamb,J.R., Skidmore, B.J.,Green, N., Chiller, J.M. and Exp. Path. 19, 137 3 Karray,S., Lymberi, P., Avrameas,S. and Coutinho, A. (1986) Feldmann, M. (1983)J. Exp. Med. 157, 1434 28 Gammon, G., Dunn, K., Shastri, N. etal. (1986)Nature 319, Stand. J. Immunol. 23,475 413 4 Cohen, I.R.,Gioberson,A. and Feldman,M. (1971)J. Exp. 29 Kappler,J.W., Roehm, N. and Marrack, P. (1987) Ce1149, Med. 133.834 273 5 Cohen. I.R.and Wekerle, H. (1973)./. EXP. Med. 137. 224
]
¢~:lusi~s
The results I have discussed show that T helper cells which recognize autologous RBC and are likely to be involved in autoimmunity exist in the normal animal. Reports from other investigators 71° support this contention. How could such cells escape deletion? It is probably not the result of an age-related decline in the efficiency of a deletion mechanism, as T cells from three-week old mice react strongly against MRBC (approximately 60% of the response given by nine-week old animals; D.C. Hooper, unpublished). By comparison, the appearance of T cells reactive against self ia antigens in adult mice appears to be a function of advancing age2s. It is unlikely that culture reactivates T cells which have been rendered anergic in vivo because T-cell clones inactivated in vitro remain so beyond the duration of the primary reaction 26. However, clonal deletion/inactivation of T cells definitely occur26-29. I suggest that this may happen with T helper cells specific for self antigens which are constitutively expressed on la-bearing cells or which can be presented in a nonimmunogenic fashion on such cells (for example, by not stimulating interleukin 1 production). I suggest, however, that T helper cells specific for self antigens which must be processed and presented to be recognized in context wi~h self la are not deleted.
i I i t
Interleukin I and T-cell adivation More than eight years have passed since the historic Second International Lymphokine Workshop in Ermatingen, Switzerland, where S. Gillis, J. Farrar, S. Mizel, V. Paetkau, K. Smith, J. Watson and D. Wood collectively gave birth to the concept of the 'interleukins'. This concept would provide the field of lymphokines with a firm foundation upon which to move from phenomenoIogy to a more refined understanding of important immunomodulators. During the past few years, the record of accomplisi,ments has been outstanding: interleuk,•s 1 and 2 have been purified, cDNAs cloned and expressed, receptors characterized and in the case of 11.-2, also cloned. We have applied our detailed understanding of the immunobiology of 11.-2 to problems in T-cell tumor biology as well as to the events that follow infection of T cells with the human immunodeficiency virus. Although the cloning of murine and human interleukin 1 (IL-1) cDNAs 1-3 has revealed the basic stru~ure ~ t ~ r ~ t University ~ r f m, ~ =. , , .n. , Lf vn{. ,=..,~vs.,.v,v~j, A,f;rrnh;n!..~'q~.,~,,.w =n,qt . . . . n,~lnnu W=~,=..... Medical Center, Winston-Salem,NC 27103, USA.
~-~.
330
,fwl, t#~l.v,~j,
...,.~
Stem B. Mizel of IL-1, as well as the existence of an IL-1 gene family, we still have no definitive picture of its role in T-cell activation. Is IL-1 an essential signal in T-cell activation or does it enhance responses triggered by specific cell surface interactions between antigen-presenting cells and T cells? What is the nature of the active species of IL-1 in T-cell activation - is it the well-characterized ~ow molecular weight form found in the culture medium of stimulated IL-l-producing cells, or a membraneassociated species? How is IL-1 production initiated during an immune response? Does the antigen- or mitogen-induced physical coupiing of T cells and accessory cells (macrophages or dendritic cells) provide a signal for the induction of IL-1 synthesis? Or do T cells release a soluble mediator that is ultimately responsible for triggering IL-1 production? Are resting T cells IL-1 responsive or do they acquire responsiveness (IL-1 receptors) after exposure to antigen or mitogen in the presence of accessory cells?
m J
© 1987. Elsevier Publications. Cambr!~ge
0 1 6 7 - 4919/871502.00
eon n en?ar -
Immunology Today, vol. 8, No. 11, 1987
On the basis of earlier results4, it was assumed that the sole task of II.-1 was to provide an essential signal which in conjunction with antigen or mitogen could trigger T-cell IL-2 production as well as IL-2 receptor expression two critical events in the pathway leading to T-cell proliferation. However, the picture today does not look so simple. For example, it remains unclear whether IL-1 is absolutely required to initiate T-cell activation. Instead of analysing the action of endogenously produced IL-1 in unfractionated cultures of lymphocytes, earlier studies focused exclusively on the effect of exogenous IL-1 in accessory cell-depleted cultures. These experiments did not show that IL-1 was essential in T-cell activation, but rather that IL-1 could reconstitute responses in the presence of limiting numbers of accessory cells. With the availability of neutralizing antibodies against murine I L - 1 , it has finally been possible to assess the contribution of endogenously produced IL-1 in T-cell activation in cultures of unfractionated lymphocytesS. The results are quite clear: anti-lL-I antibodies have no effect on T-cell proliferation induced by antigen (soluble or alloantigen) or mitogen in unfractionated populations of spleen or lymph node cells. These results are consistent with an enhancing role - as opposed to an obligatory role - for IL-1 in T-cell activation. The recent work from Koide etal. 6 supports the notion that IL-1 has a limited ability to activate T cells in the, absence of accessory cells. Using purified murine T cells at different stages of activation, II.-1 had no detectable effect on T-cell proliferation in the presence or absence of mitogens or antigens. As in earlier investigations, however, IL-1 did augment proliferation in the presence of low numbers of accessory cells, in this case, splenic dendritic cells. In the presence of optimal numbers of accessory cells, T-cell activation may be solely dependent upon a critical level of surface receptor interactions between T cells and a c c e s s o r y t-~lle i ^ proc~sed a.ug~,~c~5 ii ..... i# ~.... .. ... .. . o,,,F,,=, major histocompatibility complex (MHC) antigen and the T-cell receptor, Ly 1, L3T4 and LFA antigens). At low concentrations of accessory cells, although the number of interactions may be insufficient to trigger T-cell activation, they can act in concert with IL-1 to produce a response equivalent to that obtained with an optimal concentration of antigen-presenting accessory cells. Koide et al. 6 have made the novel suggestion that the enhancing effect of IL-1 on T-cell activation is not the result of a direct action on T cells, but instead results from stimulation of dendritic cells. This intriguing possibility deserves additional attention. Nonetheless, it is difficult to dismiss the T cell as a direct recipient of IL-I action. T cells bear high-affinity IL-1 receptors 2 and exhibit a number of metabolic responses to IL-!. For example, it has recently been shown 8 that JL-1 ac-ts in concert with phytohemagglutinin (PHA) to enhance markedly the transcription of the genes for IL-2, IL-3, the IL-2 receptor, Ly-1, transforming growth factor-13 and c-rnyc in the murine T-cell lymphoma, LBRM33-1A5. By itself, IL-1 had little if any stimulatory effect. Thus, the enhancing action of II.-1 on gene transcription is consistent with the concept of IL-1 as an enhancing factor for T-cell activation. How iL-! synthesis is induced during an immune response has also been a subject of intense study for more than a decade. A number of studies 4 indicate that T cells can induce macrophage IL-1 production in the -.'-:---
'-'---
presence of antigen or mitogens such as PHA or concanavalin A (Con A). However, a recent study by Koide and Steinrnan 9 is clearly at odds with these earlier observations. These investigators reported that lipopolysaccharide (LPS), but not tetradecanoyl phorbol 13acetate (TPA), gamma interferon, Con Ao colonystimulating factor, IL-3, tumor necrosis factor, or activated T cells could induce IL-1 gene transcription by murine macrophages. At this time, it is not possible to reconcile the results of Koide and Steinman w;th those of other investigators. I find it difficult to imagine how IL-1 is produced during immune responses if not as a result of interactions between accessory cells and T cells. The studies of Mizel et al. lo and Farr et al. il suggested that contact between accessory cells and T cells was a prerequisite for the induction of IL-1. However, two recent studies 12.13 indicate that T cells can activate IL-1 production by either cell contact or the release of a lymphokine that appears to be distinct from IL-2, gamma interferon, B-cell stimulatory factor- 1, colony-stimulatory factor-1 or tumor necrosis factor. The antigen- or mitogen-mediated coupling of T cells and accessory cells an interaction involving a complex of processed antigen, class II histocompatibility antigen and T-cell receptor may provide the intttial stimulatory signal for IL-1 production. Subsequently, activated T cells may release a lymphokine that can further up-regulate IL-1 synthesis and secretion. In 1985,~ Kurt-Jones et al. 14 identified a novel, membrane-a~sociated form of IL-1. Subsequently, a similar type! of activity was detected using paraformaldehyde-fixed tumor B cells, dendritic cells and fibroblasts, when stimulated cells were tested for bioactivity in one or more IL-1 bioassays. Conlon eta/. Is have argued that IL-I(~ rather than IL-113 is the membrane-associated form of IL-1. Although the concept of a surface membrane form of IL-1 is exciting, a note of caution is warranted. Using iodination with lactoperoxidase, it has not been possible to detect a cell surface form of IL-1 on stimulated rnacrophages (S. Mizel, unpublished). In addition, immunoprecipitation analysis of 35S-methionine-labeled macrophages has failed to detect a membrane-associated form of IL-1 at times when parallel cultures of paraformaldehyde-fixed cells exhibit bioactivity in I!.-1 assays(L. Minnich, J. Suttles and S. Mizel, unpublished). Leakage of IL-1 from fixed cells could account for the observed 'membrane IL-I' activity. Clearly, more detailed biochemical studies are required to provide a definitive statement on the question of membrane-associated IL-1. Although gaps remain in our knowledge of the function of IL-1 in T-cell activation, I offer the following working model. In tha presence of a specific antigen or T-cell mitogen, T cells and accessory cells are mutually stimulatory. The accessory cell is induced to begin IL-1 synthesis and secretion. In return, the T-cell initiates IL-2 and IL-2 receptor synthesis and expression. In addition, T cells are stimulated to produce IL-1 receptors and thus become fully responsive to IL-1. This conclusion is based upon the recent demonstration of up-regulation of IL-1 receptors on T cells incubated with stimulant and accessory cells16, IL-1 responsiveness confers upon the T cell a ......y. .to heightened o"~':~'~ . . ~,,-..,,,,,,-,"~.... I1.=1_ " "~ and IL-2 receptors ia response to processed antigen/class II MHC antigen or mitogen. Interaction between IL-2 and its receptor then results in T-cell proliferation. Activated T cells may also
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J produce a lymphokine that augments the ability of accessory cells to produce IL-1, thus providing for a secondary amplification loop in the interactions between accessory cells and T cells. When this model is put to the test, IL-1 could well provide some interesting surprises. 1 Lomedico,P.i., Gubler, U., Hellmaluh C.P.etaL (1984) Nature 312, 458-462 2 Auron. P.E.,Webb, A.C., Rosenwasser,L.J.etal. (1984)Proc NatlAcad. Sci. USA 81, 7907-7911 3 March, CJ., Mosley, B., Larsen,A. etal. (1985) Nature 315, 641-647 4 Mizel, S. (1982)Immunol. Rev. 63, 51-72 $ Mizei, S. in New Horizons in Therapeutics. Cellular and Molecular Aspects oflnflamrnation (Poste,G. and Crooke, S.T., ~:ls), PlenumPress(in press) f~ Koide, S.L, Inaba, K. and Steinman,R.M.(1987)J. Exp. Me
7 Dower, S.K., Kronheim, S.R.,March, C.J. etal. (1985)J. Exp. Med. 162, 501-515 8 Hagiwara, H., Huang. H.S.,Arai, N. etal. (1987)./. lmmunoL 138, 2514-2519 9 Koide, S. and Steinman, R.M.(1987)Proc. NatlAcad. SCL USA 84, 3802-3806 10 Mizel, S.B.,Oppenheim,J'J. and Rosenstreich,D.L. (1978) J. Immunol. 120, 1497-1503 11 Farr,A.G., Dorf, M.E. and Unanue, E.R.(1977)Proc. Natl Acad. Sci. USA 74, 3542-3546 12 Weaver, C.T. and Unanue, E.R.(1986)J. Immunol. 137, 3868-3873 13 Takacs,L., Berzofsky,J.A., York-Jolley,J. etal. (1987) J. ImmunoL 138, 2124-2131 14 Kurt-Jones,E.A., Belier, D.I., Mizel, S.B.and Unanue, E.R. (1985) Proc. NatlAcad. Sci. USA 82, 1204-1208 15 Conlon, P.J.,Grabstein, K.H., Alpert, A. etaL (1987) J. Immunol. 139, 98-102 16 Shirakawa,F., Tanaka,Y., Ota, T. etal. (1987) J. Immunol. 138. 4243-4248
s cataractformation an autoimmune phenomenon? The hypothesis that cataractogenesis is an autoimmune phenomenon is not a new one - it was suggested by Woods and Burky 1 as long ago as 1927. Recently, however, I. Angunawela at the University of Peradeniya in Sri Lanka has reopened the debate on cataract formation by reporting a significant increase in the incidence of antibody directed against lens antigens in the serum of patients with cataractous lenses and in the serum of diabetic patients2. In addition, immunoglobulin deposits could be detected on the celis of cataractous lenses removed from nondiabetic and diabetic I=atients. The close relationship betweer, diabetes and senile cataracts is a iong-standing clinical observation that takes on greater meaning in light of these recent findings. But interpreting the presence of lens-specific antibodies in the serum of catara~ous patients should be considered with caution, since similar antibodies have b~!en demonstrated in approximately 5(Ho of the norma'~ individuals tested 3.4. It is quite possible that an increased incidence of antibody directed against the lens in cataractous patients is the result of cataractogenesis and not the cause. Nonetheless, Angunawela's recent paper resurrects some interesting questions regarding the immunobiology of the lens. The notion that components of the lens are potc-ntial autoantigens was suggested more than 80 years ago by Uhlenhuth s, who demonstrated that serum ~r,~mrabbits immunized with bovine lens extracts reacted- ,~,~':,lens proteins from a wide variety of vertebrate species. Two decades later, Verhoeff and Lemoine6 suggested that such immune factors might be related to the persistent ocular inflammatory diseases that occasionally follow penetrating injury to the lens. Indeed, it has been suggested that the crystallin proteins of the lens are sequestered from the immune system early in embryonic
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Department of Ophthalmology, Universi~ of Texas Health Science Centerat Dallas, Dallas, TX 75235, USA.
JmyY. Niedeom development and thus do not induce immunological tolerance 7. Not only are the cells of the lens isolated from systemic circulation by a collagenous capsule inaccessible to blood vessels, but the lens and its capsule reside within an immunologically privileged compartment- the anterior chamber of the eye. The early sequestration of the lens during ontogeny implies that, if released into the peripheral circulation, crystallins could act as autoimmunogens in the adult. Although homologous lens proteins can elicit antibody synthesis8, attempts to demonstrate T cell-mediated immune responses to homologous lens antigens in experimental animals have been unsuccessful 9. It has been suggested that apparent T-cell tolerance to homologous crystallins may be an active process primed by exposure to low doses of homologous antigen 9. This hypothesis is supported by reports that oLand ~ crystallins can be readily detected in the aqueous humor of normal individuals 1°. Leakage of antigens from the lens into the systemic circulation may occur often enough to explain the presence of serum antibody against crystallins in approximately 50% of the normal population 3.4. Thus, it is possible that autoantigens in the lens are prevented from eliciting severe autoimmune disease by a process of active tolerance. The presence of lens-specific antibodies in many normal individuals and the appearance of crystallins in the aqueous humor of these individuals are intriguing in light of recent findings relating to the immunological privilege within the anterior chamber of the eye. It has been recognized for over a century that foreign tissue grafts can escape immunologic rejection and reside for prolonged periods within this environment 11. This 'immunological privilege' was orginally attributed to the sequestration of the graft within an anatomical compartment uniquely devoid of lymphatic drainage channels and thus (~ 1987, Elsevier Publications, Cambridge 0167 - 4919/87/$02.00