T cell activation in the context of both protective immunity and alloreactivity involves contact between the T cell receptor (TCR) and antigen presented as the peptide:MHC complex (pMHC). The strength of the TCR:pMHC interaction is quantified as TCR affinity, which has functional consequences for T cell activation. Memory T cells primed against microbial antigen can cross-react with alloantigen, a process termed heterologous immunity, due to the ability of TCR to recognize multiple pMHC with a range of affinities. Multiple in vitro studies in mouse and human have shown that alloreactive memory T cells can have a greater affinity for alloantigen than the microbial priming antigen, a finding that likely has implications for immunomodulation of alloreactive T cell responses. To investigate the functional impact of altered TCR affinity on heterologous immunity, we utilized an model in which transgenic CD8⁺ T cells are primed during an acute infection of Listeria monocytogenes expressing antigen with either high affinity or low affinity for the TCR, followed by challenge with a skin graft constitutively expressing high affinity antigen. Acute infections with high and low affinity antigen expanded primary effector CD8⁺ T cells and generated stable memory populations. During the primary effector phase, high affinity primed T cells expressed relatively more CD5 and CD27 than low affinity primed cells. At 5 weeks following infection, we challenged mice possessing memory CD8⁺ T cells that were primed with either the high or low affinity antigen with a skin graft expressing high affinity antigen. Mice primed with lower affinity antigen rejected grafts significantly faster (MST = 11.5 d) than mice primed with high affinity antigen (MST = 17 d). Compared to high affinity cells, low affinity primed memory CD8⁺ T cells expressed similar amounts of CD107a, but greater amounts of granzyme B. Ex vivo restimulation with high affinity peptide demonstrated greater granzyme B degranulation of low affinity primed memory cells. Low affinity primed memory CD8⁺ T cells expressed relatively greater amounts of CD5 and CD45RB, similar amounts of CCR7 and CXCR3, and lower levels of CD27 in comparison to high affinity primed memory. These data demonstrate that memory CD8⁺ T cells primed with low affinity antigen can become functional memory cells and can be potent effectors against high affinity antigen in the setting of alloreactivity.

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