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Classically, memory T cells arise from naive T cells after a productive immune response to a foreign pathogen in the periphery, and are poised to respond rapidly upon repeated pathogen challenge. However, in mice that have never encountered foreign pathogens, there is a substantial population of "memory-phenotype" CD8+ T cells (CD8-MP cells) that exhibit hallmarks of activation and innate-like functional properties. Due to the lack of faithful markers to distinguish CD8-MP cells from bona fide CD8+ memory T cells, the developmental origins and antigen specificities of CD8-MP cells remain incompletely defined. In this study, we used a clonal approach pairing complete TCR repertoire profiling with in-depth analysis of individual CD8-MP clones. Our findings reveal that CD8-MP cells are a distinct subset of self-reactive T cells, whose differentiation parallels the development of Foxp3+ CD4+ Treg cells in several respects. Specifically, CD8-MP differentiation is a TCR-instructed process that is triggered by the recognition of self-ligands in the thymus, occurs optimally at low clonal frequencies, and involves a multi-step process marked by an initial TCR-dependent triggering step followed by a second phase of consolidation. Developmentally, precursors expressing CD8-MP TCRs upregulate the transcription factor Eomes during thymic maturation, prior to upregulation of the full memory phenotype, providing a molecular flag for the identification of thymic CD8-MP precursors. We also used adoptive transfer and comparative TCR profiling to demonstrate that CD8-MP cells readily infiltrate oncogene-driven mouse prostate tumors and express high densities of PD-1, suggesting a previously unanticipated role for CD8-MP cells in the tumor context. Collectively, our findings challenge the common notion that CD8-MP cells differentiate from naive T cells in the periphery in lymphopenic settings, instead demonstrating that CD8-MP differentiation is a robust TCR-instructed process triggered in the thymus.




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