Location and time-dependent control of rejection by regulatory T cells culminates in a failure to generate memory T cells

被引:48
作者
Carvalho-Gaspar, Manuela [1 ]
Jones, Nick D. [1 ]
Luo, Shiqiao [1 ]
Martin, Laurent [2 ]
Brook, Matthew O. [1 ]
Wood, Kathryn J. [1 ]
机构
[1] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Surg, Transplantat Res Immunol Grp, Oxford OX3 9DU, England
[2] Univ Bourgogne, Inst Natl Sante & Rech Med Unite Mixte Rech 645, Unite Propre Rech & Enseignement Super 563, Serv Anat Pathol,Fac Med, Dijon, France
关键词
D O I
10.4049/jimmunol.180.10.6640
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Adaptive CD25(+)CD4(+) regulatory T cells (Treg) can be induced following exposure to alloantigen and may function alongside naturally occurring Treg to suppress allograft rejection when present in sufficient numbers. However, the location of the Treg as they function in vivo and the mechanisms used to control donor-reactive T cells remains ill-defined. In this study, we used a CD8(+) TCR transgenic model of skin allograft rejection to characterize in vivo activity of donor-reactive Treg cells during induction of transplantation tolerance. We demonstrate that, initially after skin transplantation, Treg attenuate the priming of donor-reactive naive CD8(+) T cells in the lymphoid tissue draining the graft site. However, with time, peripheral suppression is overcome despite the continued presence of Treg, resulting in the priming of donor-reactive CD8(+) T cells and graft infiltration by the resultant effector T cells and induction of a "Tc1-like" intragraft gene expression profile. These intragraft effector CD8(+) T cells are then prevented from eliciting rejection by Treg that simultaneously infiltrate the skin allografts, resulting in a failure to generate donor-reactive memory CD8(+) T cells. Overall, these data demonstrate for the first time that donor-reactive Treg can suppress allograft rejection using distinct mechanisms at different sites in vivo with the overall outcome of preventing the generation of donor-reactive memory T cells.
引用
收藏
页码:6640 / 6648
页数:9
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