Abstract
SUMMARYThe 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 (TCRTg101) reactive to a native C1498 leukemia cell antigen, we uncover a different mode of T cell tolerance in which TCRTg101 undergo progressive expansion and differentiation into an exhausted state. Antigen encounter by TCRTg101 requires leukemia cell major histocompatibility complex (MHC)-I expression and is independent of DCs, implying that leukemia cells directly mediate the exhausted TCRTg101 phenotype. Collectively, our data reveal that leukemia antigens are presented to CD8+ T cells via discrete pathways, leading to distinct tolerant states.
Highlights
CD8+ T cells are key effectors of anti-tumor immune responses
TCRTg101 develop along the CD8 lineage and are leukemia specific Tg101 transgenic mice were generated from T cell receptor (TCR)-a and -b chains of a CD8+ T cell clone (T15) specific for an undefined antigen expressed by C1498 leukemia cells (Boyer et al, 1997)
TCRTg101 exhibited no evidence of self-reactivity and maintained a naive phenotype that persisted in secondary lymphoid organs (SLOs) of older mice (Figures S1G–S1K)
Summary
CD8+ T cells are key effectors of anti-tumor immune responses. The degree to which tumor-specific CD8+ T cell fates are shaped by unique interactions with antigen-presenting cells (APCs) has not been well-defined. We previously demonstrated in leukemia-bearing mice that cross-presentation of a leukemia-specific antigen by splenic CD8a+ type 1 conventional dendritic cells (cDC1s) induced the deletion of a CD8+ T cell population expressing a high-affinity T cell receptor (TCR; referred to as TCR2C) (Kline et al, 2018; Zhang et al, 2013). Presentation of the antigen by cDC1s in draining lymph nodes (dLNs) of mice with locally implanted tumors derived from the same leukemia cells resulted in the robust activation of the identical CD8+ T cell population (Kline et al, 2018; Zhang et al, 2013), revealing that the environmental context in which a tumor antigen is encountered can confer drastically disparate CD8+ T cell functional states
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