Allograft rejection mediated by memory T cells is resistant to regulation.
Alloreactive memory T cells may be refractory to many of the tolerance-inducing strategies that are effective against naive T cells and thus present a significant barrier to long-term allograft survival. Because CD4(+)CD25(+) regulatory T cells (Tregs) are critical elements of many approaches to successful induction/maintenance of transplantation tolerance, we used MHC class I and II alloreactive TCR-transgenic models to explore the ability of antigen-specific Tregs to control antigen-specific memory T cell responses. Upon coadoptive transfer into RAG-1(-/-) mice, we found that Tregs effectively suppressed the ability of naive T cells to reject skin grafts, but neither antigen-unprimed nor antigen-primed Tregs suppressed rejection by memory T cells. Interestingly, different mechanisms appeared to be active in the ability of Tregs to control naive T cell-mediated graft rejection in the class II versus class I alloreactive models. In the former case, we observed decreased early expansion of effector cells in lymphoid tissue. In contrast, in the class I model, an effect of Tregs on early proliferation and expansion was not observed. However, at a late time point, significant differences in cell numbers were seen, suggesting effects on responding T cell survival. Overall, these data indicate that the relative resistance of both CD4(+) and CD8(+) alloreactive memory T cells to regulation may mediate resistance to tolerance induction seen in hosts with preexisting alloantigen-specific immunity and further indicate the multiplicity of mechanisms by which Tregs may control alloimmune responses in vivo.
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Jaeseok
J
Yang
Matthew O
MO
Brook
Manuela
M
Carvalho-Gaspar
Jidong
J
Zhang
Hilda E
HE
Ramon
Mohamed H
MH
Sayegh
Kathryn J
KJ
Wood
Laurence A
LA
Turka
Nick D
ND
Jones
D000818:Animals; D006084:Graft Rejection / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D051379:Mice; D023421:Models, Animal; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
D053645:Interleukin-2 Receptor alpha Subunit