Abstract
T cell mediated allograft rejection leads to early graft loss for kidney transplant patients. To better understand the mechanism by which T cells mediate rejection, we investigated the fate and function of graft-specific CD8 (+) T cells expressing the activated isoform of CD43 in mice and humans. Agonism of CD43 1B11 in vitro induced CD8 (+) T cell proliferation in the presence of sub-threshold antigen stimulation, and CD43 1B11 mAb treatment in vivo overcame costimulation-blockade induced tolerance to skin grafts. Relative to CD43 1B11 (-) populations, CD43 1B11 (+) CD8 (+) T cells maintained high T-bet expression along with stem-like molecules IL-7Rα and TCF-1 at both effector and memory timepoints, and were more persistent following adoptive transfer. In kidney transplant patients, graft-infiltrating CD8 (+) T cells that expressed CD43 and the glycosyltransferase GCNT1 had an effector phenotype that includes high expression of IFNG , ICOS , and perforins/granzymes. In healthy human donors and transplant candidates, the CD43 1D4 mAb clone defined antigen-experienced cytokine-producing CD8 (+) T cells. In sum, these data support a progressive differentiation model by which highly proliferative effector CD43 1B11 (+) CD8 (+) T cells infiltrate allografts also efficiently persist into memory after antigen clearance.