Autoreactivity to self H-2Kb peptides in TAP1 mice. Intravenous administration of H-2Kb class I-derived peptides induces long-term survival of grafts from C57BL/6 donors.
We and others have previously shown that TAP1-/- mice (H-2b) reject grafts from donors without major histocompatibility complex (MHC) disparity that express wild-type levels of H-2b class I molecules (C57BL/6, TAP1+/+ mice). In this same model, we also showed that subcutaneous priming of TAP1-/- mice with synthetic peptides derived from the H-2Kb molecule accelerated graft rejection and that in vivo depletion of CD4+ T cells induced a significant prolongation of graft survival, suggesting an important role for CD4 T cells. We hypothesize that, in this model, rejection is triggered by the recognition of class I molecules or derived peptides, in an inflammatory microenvironment, by a functionally altered autoreactive T-cell repertoire that escapes the control of peripheral regulatory mechanisms. In the present study, we analysed the cellular autoreactivity induced by synthetic peptides derived from the H-2Kb sequence in naive and TAP1-/- mice transplanted with C57BL/6 grafts, and investigated whether intravenous modulation of autoreactivity to these peptides induced transplantation tolerance. We showed that TAP1-/- mice have peripheral autoreactive T cells that recognize H-2Kb peptides. A significant amplification of proliferation against these peptides was detected in TAP1-/- mice that rejected grafts, indicating that the inflammatory context of transplantation induced peripheral expansion of these autoreactive T cells. Furthermore, intravenous injection of H-2Kb-derived peptides significantly prolonged graft survival in some animals. In these mice (> 100 days graft survival), we observed intragraft inhibition of interferon-gamma and interleukin-10 expression, suggesting that these cytokines have an active role during the rejection. In conclusion, our present data indicate that inflammatory autoreactive T cells directed against H-2Kb peptides can be inhibited in the periphery to prolong graft survival in TAP1-/- mice.
Marrero
Idania
I
Immunology Laboratory, Heart Institute (InCor), Sao Paulo University School of Medicine, Sao Paulo, Brazil.
Benvenutti
Luiz Alberto
LA
Kalil
Jorge
J
Coelho
Verônica
V
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000276:immunology*; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D006183:H-2 Antigens / Q000008:administration & dosage* / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007275:Injections, Intravenous; D016753:Interleukin-10 / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010455:Peptides / Q000276:immunology; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015395:Histocompatibility Antigens Class I; D010455:Peptides; C486171:Tap1 protein, mouse; D016753:Interleukin-10