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C-Myb instructs both stemness and functional exhaustion of CD8+ T cells during chronic infection [bulkRNA-seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE203575 | GEO | 2022/08/22

REPOSITORIES: GEO

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Project description:In chronic infections and cancer, exhausted CD8 T cells exhibit heterogeneous subpopulations. TCF1+PD-1+ progenitor exhausted CD8 T cells (Tpex) can self-renew and give rise to Tim-3+PD-1+ terminally differentiated CD8 T cells that retain their effector functions. Tpex cells are thus essential to maintaining a pool of antigen-specific CD8 T cells during persistent antigenic stimulation, and only they respond to PD-1-targeted therapy. Despite their potential as a crucial therapeutic target for immune interventions, the mechanisms controlling the maintenance of virus-specific Tpex cells remain to be determined. We observed approximately 10-fold fewer Tpex cells in the spleens of mice chronically infected with lymphocytic choriomeningitis virus (LCMV) one-year post-infection (p.i.) than at three months p.i. Similar to memory CD8 T cells, Tpex cells have been found to undergo self-renewal in the lymphoid organs, prominently the bone marrow, during chronic LCMV infection. Furthermore, ex vivo treatment with IL-15 preferentially induced the proliferation of Tpex cells rather than the terminally differentiated subsets. Interestingly, single-cell RNA sequencing analysis of LCMV-specific exhausted CD8 T cells after ex vivo IL-15 treatment compared with those before treatment revealed upregulation of ribosome-related genes and downregulation of genes associated with the TCR signaling pathway and apoptosis in both Tpex and Ttex subsets. The exogenous administration of IL-15 to chronically LCMV-infected mice also significantly increased self-renewal of Tpex cells in the spleen and bone marrow. In addition, we assessed the responsiveness of CD8 tumor-infiltrating lymphocytes (TILs) from renal cell carcinoma patients to IL-15. Similar to the data we obtained from chronic viral infection in mice, the expansion of the Tpex subset of PD-1+ CD8 TILs upon ex vivo IL-15 treatment was significantly higher than that of the terminally differentiated subset. These results show that IL-15 could promote self-renewal of Tpex cells, which has important therapeutic implications.

Project description:Tumors and chronic infections result in sustained antigen exposure, which promotes impaired functional responsiveness in T cells referred to as exhaustion. Checkpoint immunotherapy can induce the reinvigoration of cellular immunity by activating a recently identified precursor of exhausted T (TPEX) cell population. This activation requires cellular interactions between TPEX cells and professional antigen-presenting cells, likely conventional dendritic cells (cDC). Currently, it is unknown where cDC - TPEX cell interactions take place and which cDC subsets are involved. To address these questions, we first mapped the differentiation trajectory of TPEX cell subsets via transitory cellular states towards terminally exhausted T (TEX) cells, identified transcriptionally distinct subpopulations and defined their localization in the spleen during chronic viral infection. We found that cDC were required for TPEX cell proliferation, differentiation and viral control during PD-L1 treatment. In particular cDC1, a specialized subset of dendritic cells, colocalized with TPEX cells and regulated their maintenance by promoting the functionality of stromal cells that support TPEX cell survival. Additionally, during PD-L1 treatment, the splenic cDC1 network was significantly reorganized at the marginal zone, a site of TPEX cell differentiation. As a consequence, viral control during checkpoint immunotherapy and cellular integrity of the marginal zone depended on the presence of cDC1. Since cDC2 were sufficient to drive initial TPEX cell proliferation and TEX cell generation but not viral control, our data suggest a new concept in which cDC1 decelerate the speed of differentiation of TPEX cells via transitory cellular states and thereby generate a therapeutic window for effective immunotherapy. Together, our findings reveal how the dynamic spatial organization of the DC network supports cellular niches that guide the maintenance and differentiation of TPEX cells and opens new avenues to optimize checkpoint immunotherapy.

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C-Myb instructs both stemness and functional exhaustion of CD8+ T cells during chronic infection [bulkRNA-seq]

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