Identification of a highly functional effector CD8⁺ T cell program after transplantation in mice and humans

To better understand the mechanism by which T cells mediate allograft 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 the CD43 1B11 receptor in vitro induced CD8⁺ T cell proliferation in the presence of subthreshold antigen stimulation, and CD43 1B11 agonism in vivo overcame costimulation-blockade induced tolerance and enhanced CD8⁺ T cell cytokine production and cytotoxic function. Effector CD43 1B11⁺ CD8⁺ T cells not only expressed high levels of T-bet but also maintained Interleukin-7 receptor subunit alpha (IL-7R[alpha]), and T cell factor 1 (TCF-1) expression at both effector and memory timepoints. In adoptive transfer experiments, CD43 1B11⁺ CD8⁺ T cells were persistent following graft rechallenge and also formed TCF-1⁺IL-7Rα⁺ memory cells. Human CD8⁺ T cells expressing CD43 and the glycosyltransferase GCNT1 were present in rejecting kidney allografts and had high expression of IFNG, ICOS, and perforins/granzymes. In healthy human donors and transplant candidates, the CD43 1D4 monoclonal antibody clone defined antigen-experienced cytokine-producing CD8⁺ T cells. In sum, these data support an important role for activated CD43⁺ CD8⁺ T cells as potent effectors and point to a potential role for CD43 1B11 signaling in augmenting effector functions in the context of subthreshold antigen or costimulation.