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Loss of PBAF promotes expansion and effector differentiation of CD8+ T cells during chronic viral infection and cancer. Cell Rep 2023 Jun 27;42(6):112649

Date

06/18/2023

Pubmed ID

37330910

Pubmed Central ID

PMC10592487

DOI

10.1016/j.celrep.2023.112649

Scopus ID

2-s2.0-85162227177 (requires institutional sign-in at Scopus site)   18 Citations

Abstract

During chronic viral infection and cancer, it has been established that a subset of progenitor CD8+ T cells continuously gives rise to terminally exhausted cells and cytotoxic effector cells. Although multiple transcriptional programs governing the bifurcated differentiation trajectories have been previously studied, little is known about the chromatin structure changes regulating CD8+ T cell-fate decision. In this study, we demonstrate that the chromatin remodeling complex PBAF restrains expansion and promotes exhaustion of CD8+ T cells during chronic viral infection and cancer. Mechanistically, transcriptomic and epigenomic analyses reveal the role of PBAF in maintaining chromatin accessibility of multiple genetic pathways and transcriptional programs to restrain proliferation and promote T cell exhaustion. Harnessing this knowledge, we demonstrate that perturbation of PBAF complex constrained exhaustion and promoted expansion of tumor-specific CD8+ T cells resulting in antitumor immunity in a preclinical melanoma model, implicating PBAF as an attractive target for cancer immunotherapeutic.

Author List

Kharel A, Shen J, Brown R, Chen Y, Nguyen C, Alson D, Bluemn T, Fan J, Gai K, Zhang B, Kudek M, Zhu N, Cui W

Authors

Donia Alson Postdoctoral Researcher 2 in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Theresa Bluemn Research Scientist II in the Pediatrics department at Medical College of Wisconsin
Matthew Kudek MD Assistant Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
CD8-Positive T-Lymphocytes
Cell Differentiation
Humans
Melanoma
Mice
Transcription Factors
Virus Diseases