Abstract
The immune system must not only fight off infections, but also ensure that it does not react against its own body tissues. Since clones of lymphocytes have predetermined reactivities, some will be self-reactive and have the potential to cause damage. They should therefore be neutralized in some way. In a system as complex and important as that governing self-tolerance, many mechanisms must exist to neutralize autoaggressive lymphocytes. They may be classified under two main groups. In one the tolerant state arises from the physical or functional silencing of potentially autoaggressive lymphocytes after antigen encounter. This may involve clonal deletion, clonal abortion or clonal anergy. In the second, regulatory mechanisms of the immune system itself may hold autoreactive lymphocytes in check, for example through the operation of idiotypic network interactions and the action of specialized suppressor cells. Much evidence has accumulated for the physical deletion of autoreactive T cells as they mature in the thymus. The fate of any that escape thymus censorship has been the subject of recent research and is discussed here. Under certain conditions, self-tolerance must also be imposed at the B-cell level to prevent the production of potentially damaging autoantibodies. Although the mechanisms which silence self-reactive lymphocytes are very efficient, self-tolerance can break down, and autoimmunity will thus ensue. The main factors responsible for this are briefly described here.
Similar content being viewed by others
References
Davis MM, Bjorkman PJ: T-cell antigen receptor genes and T-cell recognition. Nature 1988;334:395.
Burnet FM: The Clonal Selection Theory of Acquired Immunity. London, Cambridge University Press, 1959.
Miller JFAP: Immunological function of the thymus. Lancet 1961;ii:748.
Miller JFAP, Mitchell GF: The thymus and the precursors of antigen-reactive cells. Nature 1967;216:659.
Berek C, Milstein C: The dynamic nature of the antibody repertoire. Immunol Rev 1988;105:5.
Fink PJ, Matis A, McElligott DL, Bookman M, Hendrick SM: Correlations between T-cell specificity and the structure of the antigen receptor. Nature 1986;321:219.
Zinkernagel RM, Doherty DC: MHC-restricted cytotoxic T cells: Studies on the biological role of polymorphic major transplantation antigens determining T cell restriction-specificity function and responsiveness. Adv Immunol 1979;27:51.
Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC: The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature 1987;329:512.
Braciale TJ, Morrison LA, Sweetser MT, Sambrook J, Gething MJ, Braciale VL: Antigen presentation pathways to class I and class II MHC-restricted T lymphocytes. Immunol Rev 1987;98:95.
Basten A: Self-tolerance: The key to autoimmunity. Proc R Soc Lond [Biol] 1989;238:1.
Sinclair NRStC: Autoreactions and autoimmunity: Rules for self-nonself discrimination. In preparation.
Scollay R, Bartlett P, Shortman K: T cell development in the adult murine thymus: Changes in the expression of the surface antigens Ly2, L3T4 and B2A2 during development from early precursor cells to emigrants. Immunol Rev 1984;82:79.
Fowlkes BJ, Edison L, Mathieson BJ, Chusel TM: Early T lymphocytes. Differentiation in vivo of adult intrathymic precursor cells. J Exp Med 1985;162:802.
Smith L: CD4+ murine T cells develop from CD8+ precursors in vivo. Nature 1987;326:798.
Kisielow P, Blüthmann H, Staerz UD, Steinmetz M, von Boehmer M, von Boehmer H: Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature 1988; 333:742.
McPhee D, Pye J, Shortman K: The differentiation of T lymphocytes. V. Evidence for intrathymic death of most thymocytes. Thymus 1979;1:151.
Sha WC, Nelson CA, Newberry RD, Kranz DM, Russell JH, Loh D: Positive and negative selection of an antigen receptor on T cells in transgenic mice. Nature 1988;336:73.
Scott B, Blüthmann H, Teh HS, von Boehmer H: The generation of mature T cells requires interaction of the αβ T-cell receptor with major histocompatibility antigens. Nature 1989;338:591.
Burnet FM, Stone JD, Edney M: The failure of antibody production in the chick embryo. Aust J Exp Biol Med Sci 1950;28:291.
Burnet FM, Fenner E: The Production of Antibodies. London, Macmillan, 1949, p 126.
Traub E: Factors influencing the persistence of choriomeningitis virus in the blood of mice after clinical recovery. J Exp Med 1938;68:229.
Owen RD: Immunogenetic consequences of vascular anastomoses between bovine twins. Science 1945; 102:400.
Billingham RE, Brent L, Medawar PO: Actively acquired tolerance of foreign cells. Nature 1953;172:603.
Scollay R, Butcher E, Weissman I: Thymus migration: Quantitative studies on the rate of migration of cells from the thymus to the periphery in mice. Eur J Immunol 1980; 10:210.
Osmond DG: Population dynamics of bone marrow B lymphocytes. Immunol Rev 1986;93:103.
Lederberg J: Genes and antibodies. Science 1959;129:1649.
Nossal GJV: The immunological response of foetal mice to influenza virus. Aust J Exp Biol Med Sci 1957; 35:549.
Kinutani M, Cotley M, le Douarin NM: Postnatal development of a demyelinating disease in avian spinal cord chimeras. Cell 1986;45:307.
Dresser DW, Mitchison NA: The mechanism of immunological paralysis. Adv. Immunol 1968;8:129.
Roelants GE, Goodman JW: Tolerance induction by an apparently non-immunogenic molecule. Nature 1970;227:175.
Gershon RK: T-cell control of antibody production. Contemp Top Immunobiol 1974;3:1.
Loblay RH, Pritchard-Briscoe H, Basten A: Memory in suppressor T cells. Nature 1978;272:620.
Möller G: Do suppressor T cells exist? Scand J Immunol 1988;27:247.
Müler JFAP, Morahan G, Allison J: Extra-thymic acquisition of tolerance by T lymphocytes: Is suppression involved? Proc Immunol 1989; 7:882.
Kappler JW, Roehm M, Marrack P: T cell tolerance by clonal elimination in the thymus. Cell 1987;49:273.
Kappler JW, Staerz U, White J, Marrack P: Self tolerance eliminates T cells specific for the Mis modified products of the major histocompatibility complex. Nature 1988;332:35.
MacDonald HR, Sneider R, Lees RK, Howe RC, Acha-Orbea H, Fetenstein H, Zinkernagel RM, Hengartner H: T cell receptor Vβ use predicts reactivity and tolerance to Mlsα-encoded antigens. Nature 1988;332:40.
Mitchison NA. The dosage requirements for immunological paralysis by soluble proteins. Immunology 1968;15:509.
Sprent J, Webb SR: Function and specificity of T cell subsets in the mouse. Adv Immunol 1987;41:39.
von Boehmer H, Hafen K: Minor but not major histocompatibility antigens of thymus epithelium tolerize precursors of cytolytic T cells. Nature 1986;320:626.
Lo D, Sprent J: Identity of cells that imprint H-2 restricted T-cell specificity in the thymus. Nature 1986; 319:672.
Salaün J, Bandeira A, khazaai I, Calman F, Cotley M, Coutinho A, Le Douarin NM: Thymic epithelium tolerizes for histocompatibility antigens. Science 1990;247:1471.
Shimonkevitz RP, Bevan MJ: Split tolerance induced by the intrathymic adoptive transfer of thymocyte stem cells. J Exp Med 1988; 168:143.
Rammensee HG: Veto function in vitro and in vivo. Int Rev Immunol 1989;4:175.
Miller JFAP, Watson JD: Intracellalar recognition events eliminate self-reactive T cells. Scand J Immunol 1988;28:389.
Lafferty KJ, Gill RG, Babcock SK, Wang Y: Active and passive antigen presentation: Its role in the induction of tissue immunity and allograft tolerance. Prog Immunol 1986;6:1040.
Loughnan MS, Nossal GJV: Interleukin 4 and 5 control expression of IL-2 receptor on murine B cells through independent induction of its two chains. Nature 1989;340:76.
Bretscher PA, Cohn M: A theory of self-nonself discrimination: Paralysis and induction involve the recognition of one and two determinants on an antigen, respectively. Science 1970;163:1042.
Lamb JR, Skidmore BJ, Green N, Chiller JM, Feldmann M: Induction of tolerance in influenza virus-immune T lymphocyte clones with syngeneic peptides of influenza hemaglutinin. J Exp Med 1983;157:1434.
Essery G, Feldmann M, Lamb JR: Interleukin-2 can prevent and reverse antigen-induced unresponsiveness in cloned human T lymphocytes. Immunology 1988;64:413.
Schwartz RH: A cell culture model for T lymphocyte clonal anergy. Science 1990;248:1349.
Weaver CT, Unanue ER: The costimulatory function of antigen-presenting cells. Immunol Today 1990; 11:49.
Gross JA, St John T, Allison JP: The murine homologue of the T lymphocyte antigen CD28. Molecular cloning and cell surface expression. J Immunol 1990;144:3201.
Allison J, Campbell IL, Morahan G, Mandal TE, Harrison L, Miller JFAP: Diabetes in transgenic mice resulting from over-expression of class I histocompatibility molecules in pancreatic β cells. Nature 1988; 333:529.
Morahan G, Allison J, Miller JFAP: Tolerance of class 1 histocompatibility antigens expressed extra-thymically. Nature 1989;339:622.
Morahan G, Brennan F, Bhathal PS, Allison J, Cox KO, Miller JFAP: Expression in transgenic mice of class I histocompatibility antigens controlled by the metallothionein promoter. Proc Natl Acad Sci USA 1989;86:3782.
Miller JFAP, Morahan G, Allison J: Extra-thymic acquisiton of tolerance by T lymphocytes. Cold Spring Harbor Symp Quant Biol 1989;54:807.
Miller JFAP, Morahan G, Allison J, Bhathal P, Cox K, Brennan F: T cell tolerance in transgenic mice expressing major histocompatibility class I molecules in defined tissues. Immunol Rev 1989;107:109.
Sarvetnick N, Liggitt D, Pitts SL, Hansen SE, Stewart SE, Stewart TA: Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. Cell 1988;52:773.
Lo D, Burkly LC, Flavell RA, Palmiter RD, Brinster RL: Tolerance in transgenic mice expressing class II major histocompatibility complex on pancreatic acinar cells. J Exp Med 1989;170:87.
Lo D, Burkley LC, Widera G, Cowing C, Flaveli RA, Palmiter RD, Brinster RL: Diabetes and tolerance in transgenic mice expressing class II MHC molecules in pancreatic beta cells. Cell 1988;53:159.
Murphy KM, Weaver CT, Elish M, Allen PM, Loh DY: Peripheral tolerance to allogeneic class II histocompatibility antigens expressed in transgenic mice: Evidence against a clonal-deletion mechanism. Proc Natl Acad Sci USA 1989;86:10034.
Miller J, Daitch L, Rath S, Selsink E: Tissue-specific expression of allogeneic class II MHC molecules induces neither tissue reaction nor clonal inactivation of alloreactive T cells. J Immunol 1990;144:334.
Jones-Youngblood SL, Wieties K, Forman J, Hammer RE: Effect of the expression of a hepatocyte-specific MHC molecule in transgenic mice on T cell tolerance. J Immunol 1990;144:1187.
Nossal GJV: Cellular mechanism of immunologic tolerance. Annu Rev Immunol 1983;1:33.
Jenkins MK, Schwartz R: Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med 1987; 165:302.
Waldmann H, Cobbold SP, Qin S: Tolerance induction using CD4 and CD8 monoclonal antibodies. Prog Immunol 1989;7:147.
Rammensee HG, Kreschewski R, Frangouiis B: Clonal anergy induced in mature V6+ Y lymphocytes on immunizing, Mls-Ib mice with Mls-Ia expressing cells. Nature 1989; 339:541.
Dailman MJ, Shiho O, Page TH, Wood KJ, Morris PJ: Peripheral tolerance to alloantigen results from altered regulation of the interleukin pathway. J Exp Med 1991;173:79.
Simon JC, Tigelaar RE, Bergstresser PR, Edelbaum D, Cruz PD Jr: Ultraviolet B radiation converts Langerhans cells from immunogenic to tolerogenic antigen-presenting cells. Induction of specific clonal anergy in CD4+ T helper I cells. Immunol 1991;146:485.
Schönrich G, Kalinke U, Momburg F, Malissen M, Semitt-Verhulst AM, Malissen B, Hämmerling GJ, Arnold B: Downregulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction. Cell 1991;65:1.
Morahan G, Hoffmann M, Miller JFAP: A hon-deletional mechanism of peripheral tolerance in T cell receptor transgenic mice. Proc Natl Acad Sci USA 1991;88:11421.
Heath WR, Allison J, Hoffmann MW, Schönrich G, Hämmerling G, Arnold B, Miller JFAP: Autoimmune diabetes as a consequence of locally produced interleukin-2. Nature 1992;359:547.
Ohashi PS, Oehen S, Buerki K, Pircher H, Ohashi CT, Odermatt B, Malissen B, Zinkernagel RM, Hengartner H: Abiation of ‘tolerance’ and induction of diabetes by virus infection in viral antigen transgenic mice. 1991;65:305.
Oldstone MBA, Nerenberg M, Southern P, Price J, Lewicki H: Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: Role of anti-self (virus) immune response. Cell 1991; 65:319.
Allison J, Malcolm L, Chosich N, Miller JFAP: Inflammation but not autoimmunity occurs in transgenic mice expressing constitutive levels of IL-2 in islet β cells. Eur J Immunol 1992;22:1115.
Harris DE, Cairns L, Rosen FS, Borel Y: A natural model of immunological tolerance: Tolerance to murine C5 is mediated by T cells and antigen is required to maintain unresponsiveness. J Exp Med 1983; 156:567.
Whiteley PJ, Poindexter NJ, Landon C, Kapp JA: A peripheral mechanism preserves self-tolerance to a secreted protein in transgenic mice. J Immunol 1990;145:1376.
Goodnow CC, Adelstein S, Basten A: The need for central and peripheral tolerance in the B cell repertoire. Science 1990;248:1373.
Nossal GJV, Pike B: Clonal anergy: Persistence in tolerant mice of antigen-binding B lymphocytes incapable of responding to antigen or mitogen. Proc Natl Acad Sci USA 1980; 77:1602.
Goodnow CC, Crosbie J, Adelstein S, Lavoie TB, Smith-Gill SJ, Mason DY, Jorgensen H, Brink RA, Pritchard-Briscoe H, Loughnan M, Loblay RH, Trent RJ, Basten A: Clonal silencing of self-reactive B lymphoytes in a transgenic mouse model. Cold Spring Harbor Symp Quant Biol 1989;54:907.
Goodnow CC, Crosbie J, Jorgensen H, Brink RA, Basten A: Induction of self-tolerance in mature peripheral B lymphocytes. Nature 1989;342:385.
Adelstein S, Pritchard-Briscoe H, Anderson TA, Crosbie J, Gammon G, Loblay RH, Basten A, Goodnow CC: Induction of self-tolerance in T cells but not in B cells of transgenic mice expressing little self antigen. Science 1991;251:1223.
Adams E, Basten A, Goodnow CC: Intrinsic B-cell hyporesponsiveness accounts for self-tolerance in lysozyme/antilysozyme double transgenic mice. Proc Natl Acad Sci USA 1990;87:5687.
Nemazee DA, Bürki K: Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature 1989; 337:562.
Nemazee DA, Russell D, Arnold B, Hämmerling G, Allison J, Miller JFAP, Morahan G, Bürki K: Clonal deletion of autospecific B lymphocytes. Immunol Rev 1991;122:117.
Ehrlich P: On immunity with special reference to cell life. Proc R Soc Lond [Biol] 1990;66:424.
Todd JA, Bell JI, McDevitt HO: HLA-DQ β gene contributes to susceptibility and resistance in insulin-dependent diabetes mellitus. Nature 1987;329:599.
Bacelj A, Charlton B, Mandel TE: Prevention of cyclophosphamide-induced diabetes by anti-Vβ8 T-lymphocyte-receptor monoclonal antibody therapy in NOD/Wehi mice. Diabetes 1989;38:1492.
Biddison WE, Beall SS, Concannon P, Charmley P, Gatti RA, Hood LE, McFarland HF, McFarlin DE: The germiine repertoire of T cell receptor β chain genes in patients with multiple sclerosis. Res Immunol 1989;140:212.
Nishimoto H, Kikutani H, Yamamura K, Kishimoto T: Prevention of autoimmune insulitis by expression of I-E molecules in NOD mice. Nature 1987;328:432.
Böhme J, Schuhbaur B, Kanagawa O, Benoist C, Mathis D: MHC-linked protection from diabetes dissociated from clonal deletion of T cells. Science 1990;249:293.
Lund T, O'Reilly L, Hutchings P, Kanagawa O, Simpson F, Gravely R, Chandler P, Dyson J, Picard JK, Edwards A, Kicussis D, Cooke A: Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A β-chain or normal I-E α-chain. Nature 1990;345:727.
Miyazaki T, Uno M, Uehira KM, Kikutani H, Kishimoto T, Kimoto M, Nishimoto H, Miyazaki J, Yamamura K: Direct evidence for the contribution of the unique I-ANOD to the development of insulitis in non-obese diabetic mice. Nature 1990;345:722.
Slattery R, Kjer-Nielsen L, Allison J, Charlton B, Mandel TE, Miller JFAP: Prevention of diabetes in NOD/Lt-I-Ak transgenic mice. Nature 1990;345:724.
Reich EP, Sherwin RS, Kanagawa O, Janeway CA: An explanation for the protective effect of the MHC class II I-E molecule in murine diabetes. Nature 1989;341:326.
Haskins K, McDuffie M: Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone. Science 1990;249:1433.
Chariton B, Baceli A, Slattery RM, Mandel TE: Cyclophosphamide induced diabetes in NOD/WEHI mice. Evidence for suppression in spontaneous autoimmune diabetes mellitus. Diabetes 1989;38:441.
Boitard C, Yasunami R, Dardenne M, Bach JF: T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice. J Exp Med 1989;169:1669.
Chandy KG, Charles AM, Kershnar A, Buckingham B, Waldeck N, Gupta S: Autologous mixed lymphocyte reaction in man: XV. Cellular and molecular basis of deficient autologous mixed lymphocyte response in insulin-dependent diabetes mellitus. J Clin Immunol 1984;4:424.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Miller, J.F.A.P. Self-nonself discrimination and tolerance in T and B lymphocytes. Immunol Res 12, 115–130 (1993). https://doi.org/10.1007/BF02918299
Issue Date:
DOI: https://doi.org/10.1007/BF02918299