Class I-restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8(+) T cells
C Kurts, H Kosaka, F R Carbone, J F Miller, W R Heath, C Kurts, H Kosaka, F R Carbone, J F Miller, W R Heath
Abstract
In this report, we show that cross-presentation of self-antigens can lead to the peripheral deletion of autoreactive CD8(+) T cells. We had previously shown that transfer of ovalbumin (OVA)-specific CD8(+) T cells (OT-I cells) into rat insulin promoter-membrane-bound form of OVA transgenic mice, which express the model autoantigen OVA in the proximal tubular cells of the kidneys, the beta cells of the pancreas, the thymus, and the testis of male mice, led to the activation of OT-I cells in the draining lymph nodes. This was due to class I-restricted cross-presentation of exogenous OVA on a bone marrow-derived antigen presenting cell (APC) population. Here, we show that adoptively transferred or thymically derived OT-I cells activated by cross-presentation are deleted from the peripheral pool of recirculating lymphocytes. Such deletion only required antigen recognition on a bone marrow-derived population, suggesting that cells of the professional APC class may be tolerogenic under these circumstances. Our results provide a mechanism by which the immune system can induce CD8(+) T cell tolerance to autoantigens that are expressed outside the recirculation pathway of naive T cells.
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References
- Wooley PH, Luthra HS, Stuart JM, David CS. Type II collagen-induced arthritis in mice. I. Major histocompatibility complex (I region) linkage and antibody correlates. J Exp Med. 1981;154:688–700.
- Zamvil SS, Steinman L. The T lymphocyte in experimental allergic encephalomyelitis. Annu Rev Immunol. 1990;8:579–621.
- Ohashi PS, Oehen S, Buerki K, Pircher H, Ohashi CT, Odermatt B, Malissen B, Zinkernagel RM, Hengartner H. Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice. Cell. 1991;65:305–317.
- Oldstone MB, 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;65:319–331.
- Schonrich G, Kalinke U, Momburg F, Malissen M, Schmitt-Verhulst AM, Malissen B, Hammerling GJ, Arnold B. Down-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction. Cell. 1991;65:293–304.
- Schonrich G, Momburg F, Malissen M, Schmitt-Verhulst AM, Malissen B, Hammerling GJ, Arnold B. Distinct mechanisms of extrathymic T cell tolerance due to differential expression of self antigen. Int Immunol. 1992;4:581–590.
- Schonrich G, Alferink J, Klevenz A, Kublbeck G, Auphan N, Schmitt-Verhulst AM, Hammerling GJ, Arnold B. Tolerance induction as a multi-step process. Eur J Immunol. 1994;24:285–293.
- Fields LE, Loh DY. Organ injury associated with extrathymic induction of immune tolerance in doubly transgenic mice. Proc Natl Acad Sci USA. 1992;89:5730–5734.
- Heath WR, Allison J, Hoffmann MW, Schonrich G, Hammerling G, Arnold B, Miller JF. Autoimmune diabetes as a consequence of locally produced interleukin-2. Nature (Lond) 1992;359:547–549.
- Heath WR, Karamalis F, Donoghue J, Miller JF. Autoimmunity caused by ignorant CD8+T cells is transient and depends on avidity. J Immunol. 1995;155:2339–2349.
- Lo D, Freedman J, Hesse S, Palmiter RD, Brinster RL, Sherman LA. Peripheral tolerance to an islet cell– specific hemagglutinin transgene affects both CD4+ and CD8+T cells. Eur J Immunol. 1992;22:1013–1022.
- Fowell D, Mason D. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+T cell subset that inhibits this autoimmune potential. J Exp Med. 1993;177:627–636.
- Guerder S, Meyerhoff J, Flavell R. The role of the T cell costimulator B7-1 in autoimmunity and the induction and maintenance of tolerance to peripheral antigen. Immunity. 1994;1:155–166.
- Bertolino P, Heath WR, Hardy CL, Morahan G, Miller JF. Peripheral deletion of autoreactive CD8+ T cells in transgenic mice expressing H-2Kbin the liver. Eur J Immunol. 1995;25:1932–1942.
- Mackay CR. Homing of naive, memory and effector lymphocytes. Curr Opin Immunol. 1993;5:423–427.
- Ferber I, Schonrich G, Schenkel J, Mellor AL, Hammerling GJ, Arnold B. Levels of peripheral T cell tolerance induced by different doses of tolerogen. Science (Wash DC) 1994;263:674–676.
- Germain RN. MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation. Cell. 1994;76:287–299.
- Bevan MJ. Antigen presentation to cytotoxic T lymphocytes in vivo. J Exp Med. 1995;182:639–641.
- Rock KL. A new foreign policy: MHC class I molecules monitor the outside world. Immunol Today. 1996;17:131–137.
- Bevan MJ. Cross-priming for a secondary cytotoxic response to minor H antigens with H-2 congenic cells which do not cross-react in the cytotoxic assay. J Exp Med. 1976;143:1283–1288.
- Gordon RD, Mathieson BJ, Samelson LE, Boyse EA, Simpson E. The effect of allogeneic presensitization on H-Y graft survival and in vitro cell-mediated responses to H-y antigen. J Exp Med. 1976;144:810–820.
- Gooding LR, Edwards CB. H-2 antigen requirements in the in vitro induction of SV40-specific cytotoxic T lymphocytes. J Immunol. 1980;124:1258–1262.
- von Boehmer H, Hafen K. Minor but not major histocompatibility antigens of thymus epithelium tolerize precursors of cytolytic T cells. Nature (Lond) 1986;320:626–628.
- Carbone FR, Bevan MJ. Class I–restricted processing and presentation of exogenous cell-associated antigen in vivo. J Exp Med. 1990;171:377–387.
- Huang AY, Golumbek P, Ahmadzadeh M, Jaffee E, Pardoll D, Levitsky H. Role of bone marrow–derived cells in presenting MHC class I–restricted tumor antigens. Science (Wash DC) 1994;264:961–965.
- Arnold D, Faath S, Rammensee H, Schild H. Cross-priming of minor histocompatibility antigen-specific cytotoxic T cells upon immunization with the heat shock protein gp96. J Exp Med. 1995;182:885–889.
- Kurts C, Heath WR, Carbone FR, Allison J, Miller JFAP, Kosaka H. Constitutive class I–restricted exogenous presentation of self antigens in vivo. J Exp Med. 1996;184:923–930.
- Hogquist KA, Jameson SC, Heath WR, Howard JL, Bevan MJ, Carbone FR. T cell receptor antagonist peptides induce positive selection. Cell. 1994;76:17–27.
- Lyons AB, Parish CR. Determination of lymphocyte division by flow cytometry. J Immunol Meth. 1994;171:131–137.
- Hodgkin PD, Lee JH, Lyons AB. B cell differentiation and isotype switching is related to division cycle number. J Exp Med. 1996;184:277–281.
- Fulcher DA, Lyons AB, Korn SL, Cook MC, Koleda C, Parish C, Fazekas de St B, Groth, Basten A. The fate of self-reactive B cells depends primarily on the degree of antigen receptor engagement and availability of T cell help. J Exp Med. 1996;183:2313–2328.
- Nikolic-Zugic J, Bevan MJ. Role of self-peptides in positively selecting the T-cell repertoire. Nature (Lond) 1990;344:65–67.
- Jondel M, Schirmbeck R, Reimann J. MHC class I–restricted CTL responses to exogenous antigens. Immunity. 1996;5:295–302.
- Webb S, Morris C, Sprent J. Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity. Cell. 1990;63:1249–1256.
- Jones LA, Chin LT, Longo DL, Kruisbeek AM. Peripheral clonal elimination of functional T cells. Science (Wash DC) 1990;250:1726–1729.
- Moskophidis D, Lechner F, Pircher H, Zinkernagel RM. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells (see erratum Nature (Lond.).1993. 364:262) Nature (Lond) 1993;362:758–761.
- Kyburz D, Aichele P, Speiser DE, Hengartner H, Zinkernagel RM, Pircher H. T cell immunity after a viral infection versus T cell tolerance induced by soluble viral peptides. Eur J Immunol. 1993;23:1956–1962.
- Mamalaki C, Tanaka Y, Corbella P, Chandler P, Simpson E, Kioussis D. T cell deletion follows chronic antigen specific T cell activation in vivo. Int Immunol. 1993;5:1285–1292.
- Critchfield JM, Racke MK, Zuniga PJ, Cannella B, Raine CS, Goverman J, Lenardo MJ. T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis. Science (Wash DC) 1994;263:1139–1143.
- Forster I, Hirose R, Arbeit JM, Clausen BE, Hanahan D. Limited capacity for tolerization of CD4+T cells specific for a pancreatic beta cell neo-antigen. Immunity. 1995;2:573–585.
- Morgan DJ, Liblau R, Scott B, Fleck S, McDevitt HO, Sarvetnick N, Lo D, Sherman LA. CD8(+)T cell– mediated spontaneous diabetes in neonatal mice. J Immunol. 1996;157:978–983.
- Husmann LA, Bevan MJ. Cooperation between helper T cells and cytotoxic T lymphocyte precursors. Ann NY Acad Sci. 1988;532:158–162.
- Guerder S, Matzinger P. A fail-safe mechanism for maintaining self-tolerance. J Exp Med. 1992;176:553–564.
- Krieger NR, Yin DP, Fathman CG. CD4+ but not CD8+cells are essential for allorejection. J Exp Med. 1996;184:2013–2018.
- Kirberg J, Bruno L, von Boehmer H. CD4+8− help prevents rapid deletion of CD8+cells after a transient response to antigen. Eur J Immunol. 1993;23:1963–1967.
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