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The timing of differentiation and potency of CD8 effector function is set by RNA binding proteins

Author

Listed:
  • Georg Petkau

    (Immunology Programme, The Babraham Institute, Babraham Research Campus)

  • Twm J. Mitchell

    (Immunology Programme, The Babraham Institute, Babraham Research Campus)

  • Krishnendu Chakraborty

    (Immunology Programme, The Babraham Institute, Babraham Research Campus)

  • Sarah E. Bell

    (Immunology Programme, The Babraham Institute, Babraham Research Campus)

  • Vanessa D´Angeli

    (Immunology Programme, The Babraham Institute, Babraham Research Campus)

  • Louise Matheson

    (Immunology Programme, The Babraham Institute, Babraham Research Campus)

  • David J. Turner

    (Immunology Programme, The Babraham Institute, Babraham Research Campus)

  • Alexander Saveliev

    (Immunology Programme, The Babraham Institute, Babraham Research Campus)

  • Ozge Gizlenci

    (Immunology Programme, The Babraham Institute, Babraham Research Campus)

  • Fiamma Salerno

    (Immunology Programme, The Babraham Institute, Babraham Research Campus)

  • Peter D. Katsikis

    (Erasmus University Medical Center)

  • Martin Turner

    (Immunology Programme, The Babraham Institute, Babraham Research Campus)

Abstract

CD8+ T cell differentiation into effector cells is initiated early after antigen encounter by signals from the T cell antigen receptor and costimulatory molecules. The molecular mechanisms that establish the timing and rate of differentiation however are not defined. Here we show that the RNA binding proteins (RBP) ZFP36 and ZFP36L1 limit the rate of differentiation of activated naïve CD8+ T cells and the potency of the resulting cytotoxic lymphocytes. The RBP function in an early and short temporal window to enforce dependency on costimulation via CD28 for full T cell activation and effector differentiation by directly binding mRNA of NF-κB, Irf8 and Notch1 transcription factors and cytokines, including Il2. Their absence in T cells, or the adoptive transfer of small numbers of CD8+ T cells lacking the RBP, promotes resilience to influenza A virus infection without immunopathology. These findings highlight ZFP36 and ZFP36L1 as nodes for the integration of the early T cell activation signals controlling the speed and quality of the CD8+ T cell response.

Suggested Citation

  • Georg Petkau & Twm J. Mitchell & Krishnendu Chakraborty & Sarah E. Bell & Vanessa D´Angeli & Louise Matheson & David J. Turner & Alexander Saveliev & Ozge Gizlenci & Fiamma Salerno & Peter D. Katsikis, 2022. "The timing of differentiation and potency of CD8 effector function is set by RNA binding proteins," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29979-x
    DOI: 10.1038/s41467-022-29979-x
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    References listed on IDEAS

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    1. Qinghong Wang & Huan Ning & Hui Peng & Lin Wei & Rong Hou & Daniel F. Hoft & Jianguo Liu, 2017. "Tristetraprolin inhibits macrophage IL-27-induced activation of antitumour cytotoxic T cell responses," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    2. Dietmar Zehn & Sarah Y. Lee & Michael J. Bevan, 2009. "Complete but curtailed T-cell response to very low-affinity antigen," Nature, Nature, vol. 458(7235), pages 211-214, March.
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    1. Pingfen Zhu & Weiqiang Liu & Xiaoxiao Zhang & Meng Li & Gaoming Liu & Yang Yu & Zihao Li & Xuanjing Li & Juan Du & Xiao Wang & Cyril C. Grueter & Ming Li & Xuming Zhou, 2023. "Correlated evolution of social organization and lifespan in mammals," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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