Heterologous immunity, defined as a process during which microbe-specific T cells cross-react with allogeneic antigen and mediate graft rejection, is recognized as a significant barrier to transplant tolerance. During the process of heterologous allorecognition, the TCR affinity for the priming ligand is likely to differ from the TCR affinity of the ligand recognized during secondary recall; however, little is known about the effect of low affinity priming on memory cell generation and function. To interrogate the impact of TCR affinity in costimulation blockade-resistant T cell mediated graft rejection during heterologous immunity, we utilized an antigen-specific model of memory CD8+ T cell mediated graft rejection in which T cells are primed with either a high or low affinity antigen. Interestingly, both high and low affinity priming elicited costimulation blockade resistant graft rejection. We next investigated the mechanism by which low affinity-primed memory T cells mediated costimulation blockade-resistant rejection. We found that low affinity primed memory T cells produced higher levels of TNF in response to heterologous rechallenge as compared to high affinity primed memory CD8+ T cells. Attenuation of TNF signaling is recognized as an effective means of therapy for autoimmune diseases, but the role of the TNF pathway in both transplantation and low affinity T cell responses is not known. We found that while TNFR2 expression was similar on primary effectors, low affinity secondary effectors significantly significantly upregulated surface TNFR2 expression. Blockade of TNFR2 attenuated graft rejection in low but not high affinity primed animals. Together, these results demonstrate that low affinity priming results in a differentiation program that relies on TNF signaling and requires TNFR for optimum secondary recall responses. Thus, TNFR2:TNF signaling represents a novel mechanism by which low affinity primed cross-reactive memory T cells can mediate heterologous immunity and graft rejection. These data establish a functional connection between TNF signaling and TCR priming affinity and have implications for the immunomodulation of pathogenic T cell responses during transplantation.

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