c-Myb instructs both stemness and functional exhaustion of CD8 + T cells during chronic infection

Chronic viral infections and tumors are associated with CD8 + T cell exhaustion, a statecharacterized by high expression of inhibitory receptors such as programmed cell death protein1 (PD-1) and impaired effector function. Chronically activated CD8 + T cells are maintained byprecursors of exhausted T (TPEX) cells that express the transcription factor TCF1 andconcurrently self-renew and give rise to TCF1– exhausted effector T (TEX) cells. Here, weuncover that long-term self-renewal capacity, multipotency and repopulation potential areselectively preserved in a small population of transcriptionally distinct CD62L + TPEX cellsduring chronic infection. We show that the transcription factor c-Myb is essential for thedevelopment of CD62L+ TPEX cells and long-term maintenance of the TCF1+ TPEX cellcompartment. Furthermore, c-Myb is required to limit early expansion of antigen-specific Tcells and induce functional T cell exhaustion. Consequently, mice that lack c-Myb specificallyin their T cells succumb to chronic but not acute viral infection. Finally, we show that theproliferative burst in response to PD-1 checkpoint inhibition originates exclusively fromCD62L + TPEX cells and depends on c-Myb. Thus, our findings identify CD62L + TPEX cellsas central to the maintenance of T cell responses to chronic viral infection and reveal c-Myb asa transcriptional orchestrator of two fundamental aspects of exhausted T cell responses, down-regulation of effector function and long-term preservation of T cell self-renewal capacity.