1. Academic Validation
  2. cBAF complex components and MYC cooperate early in CD8+ T cell fate

cBAF complex components and MYC cooperate early in CD8+ T cell fate

  • Nature. 2022 Jul;607(7917):135-141. doi: 10.1038/s41586-022-04849-0.
Ao Guo  # 1 Hongling Huang  # 1 Zhexin Zhu 2 Mark J Chen 1 Hao Shi 1 Sujing Yuan 1 Piyush Sharma 1 Jon P Connelly 3 Swantje Liedmann 1 Yogesh Dhungana 1 Zhenrui Li 1 Dalia Haydar 4 Mao Yang 1 Helen Beere 1 Jason T Yustein 5 Christopher DeRenzo 4 Shondra M Pruett-Miller 3 Jeremy Chase Crawford 1 Giedre Krenciute 4 Charles W M Roberts 2 Hongbo Chi 6 Douglas R Green 7
Affiliations

Affiliations

  • 1 Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 2 Comprehensive Cancer Center and Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 3 Center for Advanced Genome Engineering, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 4 Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 5 Baylor Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
  • 6 Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. hongbo.chi@stjude.org.
  • 7 Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. douglas.green@stjude.org.
  • # Contributed equally.
Abstract

The identification of mechanisms to promote memory T (Tmem) cells has important implications for vaccination and anti-cancer immunotherapy1-4. Using a CRISPR-based screen for negative regulators of Tmem cell generation in vivo5, here we identify multiple components of the mammalian canonical BRG1/BRM-associated factor (cBAF)6,7. Several components of the cBAF complex are essential for the differentiation of activated CD8+ T cells into T effector (Teff) cells, and their loss promotes Tmem cell formation in vivo. During the first division of activated CD8+ T cells, cBAF and MYC8 frequently co-assort asymmetrically to the two daughter cells. Daughter cells with high MYC and high cBAF display a cell fate trajectory towards Teff cells, whereas those with low MYC and low cBAF preferentially differentiate towards Tmem cells. The cBAF complex and MYC physically interact to establish the chromatin landscape in activated CD8+ T cells. Treatment of naive CD8+ T cells with a putative cBAF inhibitor during the first 48 h of activation, before the generation of chimeric antigen receptor T (CAR-T) cells, markedly improves efficacy in a mouse solid tumour model. Our results establish cBAF as a negative determinant of Tmem cell fate and suggest that manipulation of cBAF early in T cell differentiation can improve Cancer Immunotherapy.

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