Divergent fates of antigen-specific CD8+ T cell clones in mice with acute leukemia

The existence of a dysfunctional CD8⁺ T cell state in Cancer is well established. However, the degree to which CD8⁺ T cell fates are influenced by the context in which they encounter cognate tumor antigen is less clear. We previously demonstrated that CD8⁺ T cells reactive to a model leukemia antigen were deleted by antigen cross-presenting type 1 conventional dendritic cells (cDC1s). Here, through a study of T cell receptor (TCR) transgenic CD8⁺ T cells (TCR_Tg101) reactive to a native C1498 leukemia cell antigen, we uncover a different mode of T cell tolerance in which TCR_Tg101 undergo progressive expansion and differentiation into an exhausted state. Antigen encounter by TCR_Tg101 requires leukemia cell major histocompatibility complex (MHC)-I expression and is independent of DCs, implying that leukemia cells directly mediate the exhausted TCR_Tg101 phenotype. Collectively, our data reveal that leukemia antigens are presented to CD8⁺ T cells via discrete pathways, leading to distinct tolerant states.