The SWI/SNF chromatin remodeling complexes BAF and PBAF differentially regulate epigenetic transitions in exhausted CD8+ T cells

• Published in: Immunity (Cambridge, Mass.) Mass.), 2023-06, Vol.56 (6), p.1320-1340.e10
• Main Authors: Baxter, Amy E., Huang, Hua, Giles, Josephine R., Chen, Zeyu, Wu, Jennifer E., Drury, Sydney, Dalton, Katherine, Park, Simone L., Torres, Leonel, Simone, Brandon W., Klapholz, Max, Ngiow, Shin Foong, Freilich, Elizabeth, Manne, Sasikanth, Alcalde, Victor, Ekshyyan, Viktoriya, Berger, Shelley L., Shi, Junwei, Jordan, Martha S., Wherry, E. John
• Format: Article
• Language: English
• Subjects: BAF; CD8-Positive T-Lymphocytes; Cell Differentiation; Chromatin; Chromatin Assembly and Disassembly; chromatin remodelling complexes; CRISPR-Cas9 screen; Epigenesis, Genetic; epigenetics; immunotherapy; PBAF; SWI/SNF; T cell exhaustion; T cell memory
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2023.05.008

CD8+ T cell exhaustion (Tex) limits disease control during chronic viral infections and cancer. Here, we investigated the epigenetic factors mediating major chromatin-remodeling events in Tex-cell development. A protein-domain-focused in vivo CRISPR screen identified distinct functions for two versions of the SWI/SNF chromatin-remodeling complex in Tex-cell differentiation. Depletion of the canonical SWI/SNF form, BAF, impaired initial CD8+ T cell responses in acute and chronic infection. In contrast, disruption of PBAF enhanced Tex-cell proliferation and survival. Mechanistically, PBAF regulated the epigenetic and transcriptional transition from TCF-1+ progenitor Tex cells to more differentiated TCF-1− Tex subsets. Whereas PBAF acted to preserve Tex progenitor biology, BAF was required to generate effector-like Tex cells, suggesting that the balance of these factors coordinates Tex-cell subset differentiation. Targeting PBAF improved tumor control both alone and in combination with anti-PD-L1 immunotherapy. Thus, PBAF may present a therapeutic target in cancer immunotherapy. [Display omitted] •SWI/SNF complexes direct distinct epigenetic checkpoints in CD8+ T cell exhaustion•PBAF protects the pool of stem-cell-like progenitor exhausted CD8+ T cells•PBAF coordinates epigenetic transitions between exhausted CD8+ T cell subsets•Depleting PBAF in CD8+ T cells improves tumor control with immunotherapy Epigeneic factors regulate key transitions in CD8+ T cell exhaustion. Baxter et al. find that two versions of SWI/SNF chromatin-remodeling complexes direct distinct epigenetic checkpoints in the development of exhaustion. Whereas BAF is required for early responses, PBAF protects the stem-cell-like population responsive to PD-1 checkpoint blockade.