MYB orchestrates T cell exhaustion and response to checkpoint inhibition

Chronic viral infections and tumours are associated with CD8+ T cell exhaustion, which is characterized by high expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and impaired effector function. Understanding the molecular regulation of T cell exhaustion is critical for the development of new immunotherapies. Chronically activated T cells are maintained by precursors of exhausted T (TPEX) cells that express the transcription factor TCF1, self-renew and give rise to TCF-1– exhausted effector T (TEX) cells; this process is currently, however, poorly understood. Here, we reveal that TPEX cells are heterogenous and contain a population of CD62L+ stem-like exhausted T cells that selectively preserve long-term self-renewal capacity and multipotency of antigen-specific T cells during chronic infection. Furthermore, we show that the transcription factor c-Myb is essential for the development of CD62L+ TPEX cells, self-renewal of TPEX cells and the induction of key features of T cell exhaustion. Consequently, Myb-deficient CD8+ T cells show uninhibited cytokine production resulting in fatal immunopathology in response to chronic but not acute LCMV infection and fail to be maintained long-term. Finally, we show that c-Myb-dependent CD62L+ TPEX cells exclusively mediate T cell proliferation during PD-1 checkpoint inhibition and show enhanced antiviral properties, making them attractive targets for new immunotherapeutic strategies. Thus, our findings identify CD62L+ TPEX cells as central to the maintenance of exhausted T cell responses and reveal c-Myb as a key transcriptional orchestrator that combines two central aspects of T cell exhaustion, limitation of T cell function and long-term maintenance during chronic infection. RNA sequencing of CD62Lpos TPEX (Ly108+TIM3-CD62L+), CD62Lneg TPEX (Ly108+TIM3-CD62L-) and TEX (Ly108-TIM3+) P14 T cells obtained from LCMV Docile infected mice on day 7 p.i..