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

Author

Listed:
  • Ao Guo

    (St Jude Children’s Research Hospital)

  • Hongling Huang

    (St Jude Children’s Research Hospital)

  • Zhexin Zhu

    (St Jude Children’s Research Hospital)

  • Mark J. Chen

    (St Jude Children’s Research Hospital)

  • Hao Shi

    (St Jude Children’s Research Hospital)

  • Sujing Yuan

    (St Jude Children’s Research Hospital)

  • Piyush Sharma

    (St Jude Children’s Research Hospital)

  • Jon P. Connelly

    (St Jude Children’s Research Hospital)

  • Swantje Liedmann

    (St Jude Children’s Research Hospital)

  • Yogesh Dhungana

    (St Jude Children’s Research Hospital)

  • Zhenrui Li

    (St Jude Children’s Research Hospital)

  • Dalia Haydar

    (St Jude Children’s Research Hospital)

  • Mao Yang

    (St Jude Children’s Research Hospital)

  • Helen Beere

    (St Jude Children’s Research Hospital)

  • Jason T. Yustein

    (Texas Children’s Hospital, Baylor College of Medicine)

  • Christopher DeRenzo

    (St Jude Children’s Research Hospital)

  • Shondra M. Pruett-Miller

    (St Jude Children’s Research Hospital)

  • Jeremy Chase Crawford

    (St Jude Children’s Research Hospital)

  • Giedre Krenciute

    (St Jude Children’s Research Hospital)

  • Charles W. M. Roberts

    (St Jude Children’s Research Hospital)

  • Hongbo Chi

    (St Jude Children’s Research Hospital)

  • Douglas R. Green

    (St Jude Children’s Research Hospital)

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.

Suggested Citation

  • Ao Guo & Hongling Huang & Zhexin Zhu & Mark J. Chen & Hao Shi & Sujing Yuan & Piyush Sharma & Jon P. Connelly & Swantje Liedmann & Yogesh Dhungana & Zhenrui Li & Dalia Haydar & Mao Yang & Helen Beere , 2022. "cBAF complex components and MYC cooperate early in CD8+ T cell fate," Nature, Nature, vol. 607(7917), pages 135-141, July.
    • Handle: RePEc:nat:nature:v:607:y:2022:i:7917:d:10.1038_s41586-022-04849-0
    DOI: 10.1038/s41586-022-04849-0
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    Cited by:

    1. Alexandria C. Wells & Kaito A. Hioki & Constance C. Angelou & Adam C. Lynch & Xueting Liang & Daniel J. Ryan & Iris Thesmar & Saule Zhanybekova & Saulius Zuklys & Jacob Ullom & Agnes Cheong & Jesse Ma, 2023. "Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Asif A. Dar & Dale D. Kim & Scott M. Gordon & Kathleen Klinzing & Siera Rosen & Ipsita Guha & Nadia Porter & Yohaniz Ortega & Katherine S. Forsyth & Jennifer Roof & Hossein Fazelinia & Lynn A. Spruce , 2023. "c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8+ T cell immunity," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    3. Jian-Xin Lin & Meili Ge & Cheng-yu Liu & Ronald Holewinski & Thorkell Andresson & Zu-Xi Yu & Tesfay Gebregiorgis & Rosanne Spolski & Peng Li & Warren J. Leonard, 2024. "Tyrosine phosphorylation of both STAT5A and STAT5B is necessary for maximal IL-2 signaling and T cell proliferation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. Yong Ryoul Kim & Jaegeon Joo & Hee Jung Lee & Chaelim Kim & Ju-Chan Park & Young Suk Yu & Chang Rok Kim & Do Hui Lee & Joowon Cha & Hyemin Kwon & Kimberley M. Hanssen & Thomas G. P. Grünewald & Murim , 2024. "Prion-like domain mediated phase separation of ARID1A promotes oncogenic potential of Ewing’s sarcoma," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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