Transplantation Elicits a Clonally Diverse CD8⁺T Cell Response that is Comprised of Potent CD43⁺Effectors

SUMMARYCD8+T cells mediate acute rejection of allografts, which threatens the long-term survival of transplanted organs. The factors that govern differentiation of graft-directed effector CD8+T cells could lead to targeted approaches to limit acute rejection. Using MHC Class I tetramers, we found that allogeneic CD8+T cells were present at an elevated precursor frequency in naïve mice, only modestly increased in number after grafting, and maintained high T cell receptor diversity throughout the immune response. While antigen-specific effector CD8+T cells poorly express the canonical effector marker KLRG-1, expression of the activated glycoform of CD43 defined potent effectors after transplantation. Activated CD43+effector T cells maintained high expression of ICOS in the presence of CTLA-4 Ig, and dual CTLA-4 Ig/anti-ICOS treatment prolonged graft survival. These data demonstrate that graft-specific CD8+T cells have a distinct response profile relative to anti-pathogen CD8+T cells, and that CD43 and ICOS are critical surface receptors that define potent effector CD8+T cell populations that form after transplantation.