Cytokines that regulate autoimmune responses

Current Opinion in Immunology

Volumn 11, Issue 6, 1999, Pages 670-676

  Falcone, Marika ^a   Sarvetnick, Nora ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOKINE; GAMMA INTERFERON; INTERLEUKIN 12; INTERLEUKIN 4; TRANSFORMING GROWTH FACTOR BETA;

ANTIGEN PRESENTING CELL; AUTOIMMUNITY; DISEASE PREDISPOSITION; HELPER CELL; HUMAN; IMMUNE RESPONSE; IMMUNOREGULATION; MACROPHAGE; NONHUMAN; REVIEW; T LYMPHOCYTE;

EID: 0032754990     PISSN: 09527915     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0952-7915(99)00035-7     Document Type: Review

References (77)

1. Wucherpfennig K.W., Strominger J.L. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell. 80:1995;695-705.
2. Libleau R.S., Singer S.M., McDevitt H.O. Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today. 16:1995;34-38.
3. Tian J., Olcott A.P., Hanssen L.R., Zekzer D., Middleton B., Kaufman D.L. Infectious Th1 and Th2 autoimmunity in diabetes-prone mice. Immunol Rev. 164:1998;119-127.
4. Seder R., Gazzinelli R., Sher A., Paul W. Interleukin-12 acts directly on CD4+ T cells to enhance priming for IFN-γ production and diminishes interleukin-4 inhibition of such priming. Proc Natl Acad Sci USA. 90:1993;10188-10192.
5. Manetti R., Parronchi P., Giudizi M., Piccinni M., Maggi E., Trinchieri G., Romagnani S. Natural killer cell stimulator factor (interleukin-12) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med. 177:1993;1199-1204.
6. Magram J., Connaughton S., Warrier R., Carvajal D., Wu C., Ferrante J., Stewart C., Sarmiento U., Faherty D., Gately M. IL-12-deficient mice are defective in IFN-gamma production and type 1 cytokine responses. Immunity. 4:1996;471-481.
7. Trembleau S., Germann T., Gately M.K., Adorini L. The role of IL-12 in the induction of organ-specific autoimmune diseases. Immunol Today. 16:1995;383-386.
8. Caspi R.R. IL-12 in autoimmunity. Clin Immunol Immunopathol. 88:1998;4-13.
9. Trembleau S., Penna G., Bosi E., Mortara A., Gately M.K., Adorini L. Interleukin 12 administration induces T helper type 1 cells and accelerates autoimmune diabetes in NOD mice. J Exp Med. 181:1995;817-821.
10. Leonard J.P., Waldburger K.E., Schaub R.G., Smith T., Hewson A.K., Cuzner M.L., Goldman S.J. Regulation of the inflammatory response in animal models of multiple sclerosis by interleukin-12. Crit Rev Immunol. 17:1997;545-553.
11. 2. Diabetologia. 40:1997;641-646.
12. Trembleau S., Penna G., Gregori S., Gately M.K., Adorini L. Deviation of pancreas-infiltrating cells to Th2 by interleukin-12 antagonist administration inhibits autoimmune diabetes. Eur J Immunol. 27:1997;2330-2339.
13. Leonard J.P., Waldburger K.E., Goldman S.J. Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J Exp Med. 181:1995;381-386.
14. Constantinescu C.S., Wysocka M., Hilliard B., Ventura E.S., Lavi E., Trinchieri G., Rostami A. Antibodies against IL-12 prevent superantigen-induced and spontaneous relapses of experimental autoimmune encephalomyelitis. J Immunol. 161:1998;5097-5104.
15. Yokoi H., Kato K., Kezuka T., Sakai J., Usui M., Yagita H., Okumura K. Prevention of experimental autoimmune uveoretinitis by monoclonal antibody to interleukin-12. Eur J Immunol. 27:1997;641-646.
16. Tarrant T.K., Silver P.B., Chan C.C., Wiggert B., Caspi R.R. Endogenous IL-12 is required for induction and expression of experimental autoimmune uveitis. J Immunol. 161:1998;122-127.
17. McIntyre K.W., Shuster D.J., Gillooly K.M., Warrier R.R., Connaughton S.E., Hall L.B., Arp L.H., Gately M.K., Magram J. Reduced incidence and severity of collagen-induced arthritis in interleukin-12-deficient mice. Eur J Immunol. 26:1996;2933-2938.
18. Trinchieri G. Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol. 13:1995;251-276.
19. Segal B.M., Klinman D.M., Shevach E.M. Microbial products induce autoimmune disease by an IL-12-dependent pathway. J Immunol. 158:1997;5087-5090.
20. Segal B.M., Shevach E.M. IL-12 unmasks latent autoimmune disease in resistant mice. J Exp Med. 184:1996;771-775.
21. Chang J.T., Shevach E.M., Segal B.M. Regulation of interleukin (IL)-12 receptor beta2 subunit expression by endogenous IL-12: a critical step in the differentiation of pathogenic autoreactive T cells. J Exp Med. 189:1999;969-978. This study introduces a new and intriguing hypothesis that genetic predisposition to autoimmunity could be linked to IL-12 secretion in the absence of infectious agents. The authors investigated the T-cell-induced IL-12 secretion in two strains of mice, SJL/J and B10.S, that are respectively highly susceptible and resistant to EAE. The results indicate that, in the SJL/J mice, T cells specific for MBP as well as for a foreign antigen were able to induce IL-12 secretion by APCs and IL-12-mediated upregulation of the IL-12Rβ2 subunit on the T cells through interaction of CD40 and CD40-ligand (CD40L). Conversely, in a resistant strain - such as B10.S mice - self-reactive T cells did not express the CD40L and were not able to upregulate the IL-12Rβ2 subunit unless exogenous IL-12 was added to the cultures. The presence of the IL-12Rβ2 subunit on autoreactive T cells was found to correlate with their encephalitogenic potential. Therefore, the ability of autoreactive T cells to induce IL-12 secretion and their own Th1 differentiation could predispose autoimmune-prone strains of mice to the activation of unnecessary inflammatory responses and, ultimately, to destructive autoimmunity.
22. Mueller R., Krahl T., Sarvetnick N. Pancreatic expression of interleukin-4 abrogates insulitis and autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med. 184:1996;1093-1099.
23. King C., Davies J., Mueller R., Lee M.S., Krahl T., Yeung B., O'Connor E., Sarvetnick N. TGF-beta1 alters APC preference, polarizing islet antigen responses toward a Th2 phenotype. Immunity. 8:1998;601-613.
24. Mueller R., Bradley L.M., Krahl T., Sarvetnick N. Mechanism underlying counterregulation of autoimmune diabetes by IL-4. Immunity. 7:1997;411-418.
25. Furlan R., Poliani P.L., Galbiati F., Bergami A., Grimaldi L.M., Comi G., Adorini L., Martino G. Central nervous system delivery of inter-leukin 4 by a nonreplicative herpes simplex type 1 viral vector ameliorates autoimmune demyelination. Hum Gene Ther. 9:1998;2605-2617.
26. Chen Y., Kuchroo V.K., Inobe J., Hafler D.A., Weiner H.L. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science. 265:1994;1237-1240.
27. - T cells was abolished by inhibition of either IL-4 or TGF-β activity. These results clearly suggest that cytokines that are downmodulatory for the Th1 pathway could also have an immunosuppressive quality for antibody-mediated autoimmune diseases. The authors' conclusions reinforce the view that the downmodulatory effect of IL-4 and TGF-β on autoimmunity stems from a direct immunosuppression of autoreactive T cells rather than a shift toward a Th2 phenotype.
28. Seder R.A., Paul W., Davis M., Fazekas de St Groth B. The presence of interleukin-4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice. J Exp Med. 176:1992;1091-1098.
29. Shull M., Ormsby I., Kier A., Pawlowski S., Diebold R., Yin M., Allen R., Sidman C., Proetzel G., Calvin D. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 359:1992;693-699.
30. Gallichan W.S., Balasa B., Davies J.D., Sarvetnick N. Pancreatic IL-4 expression results in islet-reactive Th2 cells that inhibit diabetogenic lymphocytes in the nonobese diabetic mouse. J Immunol. 163:1999;1696-1703.
31. Cope A.P. Regulation of autoimmunity by proinflammatory cytokines. Curr Opin Immunol. 10:1998;669-676. The author of this review carefully analyzes the extensive evidence that TNF has a protective role in T-cell-mediated autoimmunity. The review includes a detailed list of experimental models that use either TNF-transgenic or TNF-treated mice as well as TNF-knockout and TNF-depleted mice to point out a clear-cut critical role for this inflammatory cytokine in downmodulating inflammatory autoimmune diseases. Moreover, the possible mechanisms underlying TNF-mediated immunosuppression are discussed as well as the most recent experiments, both in vivo and in vitro, implicating a direct immunomodulatory effect of TNF on the TCR signaling pathway.
32. Yang X.D., Tisch R., Singer S.M., Cao Z.A., Liblau R.S., Schreiber D., McDevitt H.O. Effect of tumor necrosis factor alpha on insulin-dependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process. J Exp Med. 180:1994;995-1004.
33. + DCs were visible in the islets of RIP-TNF NOD mice that were only 10 days old. In these transgenic mice, macrophages and DCs were activated and increased their expression of co-stimulatory molecules such as CD86 and MHC class II molecules. Consequently, macrophages and DCs of transgenic RIP-TNF NOD mice demonstrated an increased ability to activate autoreactive T cells in vitro, even if the islet self-antigen was not added to the in vitro T cell cultures. This observation suggested that the presence of TNF in vivo in the islets could favor self-antigen uptake by macrophages and DCs. Additionally, the degree of maturation of DCs was increased in the RIP-TNF NOD mice and the authors proposed that the early presence of a strong inflammatory cytokine such as TNF in the pancreatic islets could promote IDDM pathogenesis by inducing DC maturation in situ.
34. Grewal I., Grewal K., Wong F., Picarella D., Janeway C. Jr., Flavell R. Local expression of transgene encoded TNFα in islets prevents autoimmune diabetes in nonobese diabetic (NOD) mice by preventing the development of auto-reactive islet-specific T cells. J Exp Med. 184:1996;1963-1974.
35. Hunger R.E., Carnaud C., Garcia I., Vassalli P., Mueller C. Prevention of autoimmune diabetes mellitus in NOD mice by transgenic expression of soluble tumor necrosis factor receptor p55. Eur J Immunol. 27:1997;255-261.
36. Liu J., Marino M.W., Wong G., Grail D., Dunn A., Bettadapura J., Slavin A.J., Old L., Bernard C.C. TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination. Nat Med. 4:1998;78-83. This report shows that lack of TNF in congenitally deficient mice predisposes to autoimmunity. B6 mice are susceptible to autoimmune demyelination induced by immunization with the myelin oligodendrocyte glycoprotein (MOG) whereas the 129 strain is completely resistant. TNF gene ablation rendered 129 mice susceptible to MOG-induced disease and also increased both clinical and hystopathological signs of inflammation and demyelination in the B6 strain of mice. Conversely, systemic administration of recombinant TNF significantly ameliorated autoimmune demyelination in these mice.
37. McSorley S.J., Soldera S., Malherbe L., Carnaud C., Locksley R.M., Flavell R.A., Glaichenhaus N. Immunological tolerance to a pancreatic antigen as a result of local expression of TNFalpha by islet beta cells. Immunity. 7:1997;401-409.
38. Zheng L., Fisher G., Miller R., Perchon J., Lynch D., Lenardo M. Induction of apoptosis in mature T cells by tumor necrosis factor. Nature. 377:1995;348-351.
39. Sytwu H., Liblau R., McDevitt H. The roles of Fas/APO-1 (CD95) and TNF in antigen-induced programmed cell death in T cell receptor transgenic mice. Immunity. 5:1996;17-30.
40. Cope A.P., Liblau R.S., Yang X.D., Congia M., Laudanna C., Schreiber R.D., Probert L., Kollias G., McDevitt H.O. Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. J Exp Med. 185:1997;1573-1584.
41. O'Hara R., Henderson S., Nagelin A. Prevention of a Th1 disease by a Th1 cytokine: IL-12 and diabetes in NOD mice. Ann N Y Acad Sci. 795:1996;241-249.
42. Tarrant T.K., Silver P.B., Wahlsten J.L., Rizzo L.V., Chan C.C., Wiggert B., Caspi R.R. Interleukin 12 protects from a T helper type 1-mediated autoimmune disease, experimental autoimmune uveitis, through a mechanism involving interferon gamma, nitric oxide, and apoptosis. J Exp Med. 189:1999;219-230. This study showed that IL-12 could unexpectedly protect against a Th1-mediated autoimmune disease such as experimental autoimmune uveitis. Interestingly, the protection from autoimmune uveitis was abolished in IFN-γ-deficient mice - suggesting that IL-12-mediated regulation of autoimmunity was obtained through IFN-γ secretion. The authors provided interesting evidence that explains possible mechanisms underlying immunoregulation mediated by proinflammatory cytokines. IL-12-treated mice had a reduced number of cells in the draining lymph nodes and reduced response to the self-antigen in vitro. Moreover, the number of apoptotic cells was increased in the draining lymph nodes of mice that received IL-12 at the time of priming with self-antigen. These findings, together with the observation that protection was lacking in Bcl-2-deficient mice, supported the hypothesis that IFN-γ hyperproduction induced by IL-12 could trigger Bcl-2-controlled apoptotic deletion of antigen-specific T cells. Since the protection was lost in mice deficient in iNOS (inducible nitric oxide synthase) the authors suggested that upregulation of iNOS and production of NO might also be required to trigger apoptosis of autoreactive T cells.
43. Gu D., Arnush M., Sawyer S., Sarvetnick N. Transgenic mice expressing IFN-gamma in pancreatic beta-cells are resistant to streptozotocin-induced diabetes. Am J Physiol. 269:1995;1089-1094.
44. Krakowski M., Owens T. Interferon-gamma confers resistance to experimental allergic encephalomyelitis. Eur J Immunol. 26:1996;1641-1646.
45. Willenborg D.O., Fordham S., Bernard C.C., Cowden W.B., Ramshaw I.A. IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J Immunol. 157:1996;3223-3227.
46. Kumar V., Sercarz E. Induction or protection from experimental autoimmune encephalomyelitis depends on the cytokine secretion profile of TCR peptide-specific regulatory CD4 T cells. J Immunol. 161:1998;6585-6591.
47. Falcone M., Yeung B., Tucker L., Rodriguez E., Sarvetnick N. A defect in IL-12-induced activation and IFN-γ secretion of peripheral natural killer T cells in nonobese diabetic mice suggests new pathogenic mechanisms for insulin-dependent diabetes mellitus (IDDM). J Exp Med. 190:1999;963-972. NKT cells have been shown to mediate immunoregulation of T-cell-mediated autoimmunity. Their defect in many autoimmune-prone strains of mice represents key evidence that they play a critical role to balance T cell responses between protective immunity and autoimmunity. In this study we have shown that the defect of the NKT cell subset in NOD mice specifically involved their IL-12-induced activation as well as IFN-γ secretion. These results provided strong evidence that a defect of the Th1 pathway, involving the NKT cell subset, could be associated with autoimmunity in NOD mice that develop spontaneous IDDM.
48. Holda J., Maier T., Claman H. Natural suppressor activity in graft-vs-host spleen and normal bone marrow is augmented by IL-2 and IFN-γ J Immunol. 137:1986;3538-3543.
49. Holda J., Maier T., Claman H. Evidence that IFN-γ is responsible for natural suppressor activity in GVHD spleen and normal bone marrow. Transplantation. 45:1988;772-777.
50. Huchet R., Bruley-Rosset M., Mathiot C., Grandjon D., Halle-Pannenko O. Involvement of interferon-γ and transforming growth factor-β in graft-vs-host reaction-associated immunosuppression. J Immunol. 150:1993;2517-2524.
51. Meyers C.M., Zhang Y. Immunomodulatory effects of interferon gamma on autoreactive nephritogenic T-cell clones. Kidney Int. 55:1999;1395-1406.
52. Liu Y., Janeway C. Interferon-γ plays a critical role in induced cell death of effector T cells: a possible third mechanism of self-tolerance. J Exp Med. 172:1990;1735-1739.
53. Ludewig B., Odermatt B., Landmann S., Hengartner H., Zinkernagel R.M. Dendritic cells induce autoimmune diabetes and maintain disease via de novo formation of local lymphoid tissue. J Exp Med. 188:1998;1493-1501.
54. Yoon J.W., Jun H.S., Santamaria P. Cellular and molecular mechanisms for the initiation and progression of beta cell destruction resulting from the collaboration between macrophages and T cells. Autoimmunity. 27:1998;109-122.
55. Lee K.U., Kim M.K., Amano K., Pak C.Y., Jaworski M.A., Mehta J.G., Yoon J.W. Preferential infiltration of macrophages during early stages of insulitis in diabetes-prone BB rats. Diabetes. 37:1988;1053-1058.
56. Walker R., Bone A., Cooke A., Baird J. Distinct macrophage subpopulations in pancreas of pre-diabetic BB/E rats: possible role for macrophages in the pathogenesis of IDDM. Diabetes. 37:1988;1623-1629.
57. Jasen A., Homo-Delarche R., Hooijkaas H., Leenen P., Dardenne M., Drexhage H. Immunohistochemical characterization of monocyte-macrophages and dendritic cells involved in the initiation of insulitis and beta-cell destruction in NOD mice. Diabetes. 43:1994;667-675.
58. Lee K.I., Amano K., Yoon J.W. Evidence for initial involvement of macrophages in development of insulitis in NOD mice. Diabetes. 37:1988;989-991.
59. 2MDP-treated NOD mice by IL-12 injection.
60. Chervonsky A., Wang Y., Wong F.S., Visintin I., Flavell R.A., Janeway C.A. Jr., Matis L.A. The role of Fas in autoimmune diabetes. Cell. 89:1997;17-24.
61. Itoh N., Imagawa A., Hanafusa T., Waguri M., Yamamoto K., Iwahashi H., Moriwaki M., Nakajima H., Miyagawa J., Namba M.et al. Requirement of Fas for the development of autoimmune diabetes in nonobese diabetic mice. J Exp Med. 186:1997;613-618.
62. Rovere P., Vallinoto C., Bondanza A., Crosti M.C., Rescigno M., Ricciardi-Castagnoli P., Rugarli C., Manfredi A.A. Bystander apoptosis triggers dendritic cell maturation and antigen-presenting function. J Immunol. 161:1998;4467-4471. The effect of apoptotic cells on DC activation and maturation was evaluated by studying the in vitro interaction between murine RMA lymphoma cells committed to apoptosis by UV irradiation and an immature DC line (D1). The results demonstrated that apoptotic cells, internalized by DCs, increased class-I- and class-II-mediated antigen-presentation as well as secretion of proinflammatory cytokines by DCs in a dose-dependent fashion.
63. Trinchieri G. IL-12 and its role in generation of Th1 cells. Immunol Today. 14:1993;335-337.
64. Kennedy M., Picha K., Shanebeck K., Anderson D., Grabstein K. Interleukin-12 regulates the proliferation of Th1, but not Th2 or Th0 clones. Eur J Immunol. 24:1994;2271-2278.
65. Sarvetnick N., Shizuru J., Liggitt D., Martin L., McIntyre B., Gregory A., Parslow T., Stewart T. Loss of pancreatic islet tolerance induced by beta-cell expression of interferon-gamma. Nature. 346:1990;844-847.
66. Gu D., O'Reilly L., Molony L., Cooke A., Sarvetnick N. The role of infiltrating macrophages in islet destruction and regrowth in a transgenic model. J Autoimmun. 8:1995;483-492.
67. Horwitz M.S., Evans C.F., McGavern D.B., Rodriguez M., Oldstone M.B.A. Primary demyelination in transgenic mice expressing interferon-gamma. Nat Med. 3:1997;1037-1041.
68. Campbell I.L., Oxbrow L., Koulmanda M., Harrison L.C. IFN-γ induces islet cell MHC antigens and enhances autoimmune, streptozotocin-induced diabetes in the mouse. J Immunol. 140:1988;1111-1116.
69. Cao H., Wolff R.G., Meltzer M.S., Crawford R.M. Differential regulation of class II MHC determinants on macrophages by IFN-gamma and IL-4. J Immunol. 143:1989;3524-3531.
70. Campbell I.L., Wong G., Schrader J., Harrison L. Interferon-gamma enhances the expression of the major histocompatibility class I antigens on mouse pancreatic beta cells. Diabetes. 34:1985;1205-1209.
71. Bergsteindottir K., Brennan A., Jessen K., Mirsky R. In the presence of dexamethasone, gamma interferon induces rat oligodendrocytes to express major histocompatibility complex class II molecules. Proc Natl Acad Sci USA. 89:1992;9054-9058.
72. Horwitz M.S., Bradley L., Harbertson J., Krahl T., Lee J., Sarvetnick N. Diabetes induced by coxsackie virus: initiation by bystander damage and not molecular mimicry. Nat Med. 4:1998;781-785. This article provides an extremely elegant two-phase model for the pathogenesis of T-cell-mediated autoimmune diseases. Coxsackie infection did not lead to total destruction of pancreatic islets and diabetes in NOD mice. However, the presence of coxsackie virus in the islets could induce the necessary bystander stimulus to activate the target tissue and present self antigens to the autoreactive T cell repertoire of BDC2.5 mice that carry a transgenic TCR specific for an islet antigen. The observation that the tissue-specific viral infection could trigger autoimmunity only in mice with an enlarged autoimmune T cell repertoire suggested that the pathogenesis of T-cell-mediated autoimmunity is characterized by two different phases. Amplification of the autoimmune T cell repertoire could happen in the periphery and be largely dependent on the genetic background of each individual. In addition, self-antigen-presentation and recruitment of autoreactive T cells in the target tissue through infection-induced bystander activation of APCs could represent a second signal that is required to trigger organ-specific autoimmunity.
73. Katz J.D., Wang B., Haskins K., Benoist C., Mathis D. Following a diabetogenic T cell from genesis through pathogenesis. Cell. 74:1993;1089-1100.
74. Andre-Schmutz I., Hindelang C., Benoist C., Mathis D. Cellular and molecular changes accompanying the progression from insulitis to diabetes. Eur J Immunol. 29:1999;245-255.
75. Goerdt S., Orfanos C.E. Other functions, other genes: alternative activation of antigen-presenting cells. Immunity. 10:1999;137-142.
76. Masurier C., Pioche-Durieu C., Colombo B., Lacave R., Lemoine F., Klatzmann D., Guigon M. Immunophenotypical and functional heterogeneity of dendritic cells generated from murine bone marrow cultured with different cytokine combinations: implications for anti-tumoral cell therapy. Immunology. 96:1999;569-577.
77. 2b receptor could represent a feed-back mechanism to downregulate macrophage activation and, in general, to control inflammatory immune responses.