Rejection of grafts without histocompatibility antigen disparity by TAP1-/- mice: a role for CD4+ T cells.
We have previously shown that TAP1-/- mice reject heart and skin grafts lacking an H-2 disparity. TAP1-/- mice, which are deficient for MHC-I molecules, probably have a T-cell repertoire with distinct reactivity to these molecules. We speculated that this rejection could be mediated by CD4+ T cells reactive to H-2(b) class I molecules, or to class I-derived peptides presented by self-APC. This hypothesis was tested in the present work. Presensitization of TAP1-/- mice with H-2K(b) peptides accelerated the rejection of C57BL/6 (H-2(b)) skin grafts (MST 13 days, P <.0057), indicating that these peptides were able to mobilize effector T cells that participate in rejection. In addition, CD4 T-cell depletion before transplantation induced a significant delay in rejection (P <.0011), showing that CD4 T cells have a major role in the rejection process, though other cells may also contribute. In conclusion, these results support our hypothesis that H-2(b) molecules may be targeted in graft rejection without an H-2 disparity. The low expression of MHC-I molecules on TAP1-/- mice may determine the selection of a T-cell repertoire that is reactive to self-MHC-I molecules, a phenomenon that is probably beyond the control of peripheral regulatory mechanisms.
Marrero
I
I
Immunology Laboratory, and Department of Pathology, Heart Institute (InCor), and Renal Division, São Paulo University School of Medicine, Institute for Investigation in Immunology, Millennium Institute, Sao Paulo, Brazil.
Benvenutti
L A
LA
Noronha
I
I
Kalil
J
J
Coelho
V
V
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D006183:H-2 Antigens / Q000276:immunology; D008212:Lymphocyte Depletion / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016038:Skin Transplantation / Q000276:immunology*; D013997:Time Factors
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; C486171:Tap1 protein, mouse