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The ubiquitin ligase Cul5 regulates CD4+ T cell fate choice and allergic inflammation

Author

Listed:
  • Binod Kumar

    (The Children’s Hospital of Philadelphia
    University of Pennsylvania)

  • Natania S. Field

    (The Children’s Hospital of Philadelphia
    Northwestern University)

  • Dale D. Kim

    (The Children’s Hospital of Philadelphia)

  • Asif A. Dar

    (The Children’s Hospital of Philadelphia)

  • Yanqun Chen

    (The Children’s Hospital of Philadelphia
    Wuxi Apptec)

  • Aishwarya Suresh

    (The Children’s Hospital of Philadelphia
    Drexel University College of Medicine)

  • Christopher F. Pastore

    (University of Pennsylvania School of Veterinary Medicine)

  • Li-Yin Hung

    (University of Pennsylvania School of Veterinary Medicine)

  • Nadia Porter

    (The Children’s Hospital of Philadelphia)

  • Keisuke Sawada

    (The Children’s Hospital of Philadelphia
    University of Cincinnati, College of Medicine)

  • Palak Shah

    (The Children’s Hospital of Philadelphia
    Harvard University)

  • Omar Elbulok

    (The Children’s Hospital of Philadelphia
    University of Pennsylvania)

  • Emily K. Moser

    (The Children’s Hospital of Philadelphia
    University of Florida)

  • De’Broski R. Herbert

    (University of Pennsylvania School of Veterinary Medicine)

  • Paula M. Oliver

    (The Children’s Hospital of Philadelphia
    University of Pennsylvania)

Abstract

Antigen encounter directs CD4+ T cells to differentiate into T helper or regulatory cells. This process focuses the immune response on the invading pathogen and limits tissue damage. Mechanisms that govern T helper cell versus T regulatory cell fate remain poorly understood. Here, we show that the E3 ubiquitin ligase Cul5 determines fate selection in CD4+ T cells by regulating IL-4 receptor signaling. Mice lacking Cul5 in T cells develop Th2 and Th9 inflammation and show pathophysiological features of atopic asthma. Following T cell activation, Cul5 forms a complex with CIS and pJak1. Cul5 deletion reduces ubiquitination and subsequent degradation of pJak1, leading to an increase in pJak1 and pSTAT6 levels and reducing the threshold of IL-4 receptor signaling. As a consequence, Cul5 deficient CD4+ T cells deviate from Treg to Th9 differentiation in low IL-4 conditions. These data support the notion that Cul5 promotes a tolerogenic T cell fate choice and reduces susceptibility to allergic asthma.

Suggested Citation

  • Binod Kumar & Natania S. Field & Dale D. Kim & Asif A. Dar & Yanqun Chen & Aishwarya Suresh & Christopher F. Pastore & Li-Yin Hung & Nadia Porter & Keisuke Sawada & Palak Shah & Omar Elbulok & Emily K, 2022. "The ubiquitin ligase Cul5 regulates CD4+ T cell fate choice and allergic inflammation," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30437-x
    DOI: 10.1038/s41467-022-30437-x
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    References listed on IDEAS

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    1. Teresa A. Soucy & Peter G. Smith & Michael A. Milhollen & Allison J. Berger & James M. Gavin & Sharmila Adhikari & James E. Brownell & Kristine E. Burke & David P. Cardin & Stephen Critchley & Courtne, 2009. "An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer," Nature, Nature, vol. 458(7239), pages 732-736, April.
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    Cited by:

    1. Xiaofeng Liao & Wenxue Li & Hongyue Zhou & Barani Kumar Rajendran & Ao Li & Jingjing Ren & Yi Luan & David A. Calderwood & Benjamin Turk & Wenwen Tang & Yansheng Liu & Dianqing Wu, 2024. "The CUL5 E3 ligase complex negatively regulates central signaling pathways in CD8+ T cells," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Haibo Zhang & Keke Xue & Wen Li & Xinyi Yang & Yusen Gou & Xiao Su & Feng Qian & Lei Sun, 2024. "Cullin5 drives experimental asthma exacerbations by modulating alveolar macrophage antiviral immunity," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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