Loss of Zfp335 triggers cGAS/STING-dependent apoptosis of post-β selection thymocytes

Jeremy J. Ratiu (), William E. Barclay, Elliot Lin, Qun Wang, Sebastian Wellford, Naren Mehta, Melissa J. Harnois, Devon DiPalma, Sumedha Roy, Alejandra V. Contreras, Mari L. Shinohara, David Wiest and Yuan Zhuang
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Jeremy J. Ratiu: Duke University, Department of Immunology
William E. Barclay: Duke University, Department of Immunology
Elliot Lin: Duke University, Department of Immunology
Qun Wang: Duke University, Department of Immunology
Sebastian Wellford: Duke University, Department of Immunology
Naren Mehta: Duke University, Department of Immunology
Melissa J. Harnois: Duke University, Department of Immunology
Devon DiPalma: Duke University, Department of Immunology
Sumedha Roy: Duke University, Department of Immunology
Alejandra V. Contreras: Fox Chase Cancer Center, Blood Cell Development and Function Program
Mari L. Shinohara: Duke University, Department of Immunology
David Wiest: Fox Chase Cancer Center, Blood Cell Development and Function Program
Yuan Zhuang: Duke University, Department of Immunology

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Production of a functional peripheral T cell compartment typically involves massive expansion of the bone marrow progenitors that seed the thymus. There are two main phases of expansion during T cell development, following T lineage commitment of double-negative (DN) 2 cells and after successful rearrangement and selection for functional TCRβ chains in DN3 thymocytes, which promotes the transition of DN4 cells to the DP stage. The signals driving the expansion of DN2 thymocytes are well studied. However, factors regulating the proliferation and survival of DN4 cells remain poorly understood. Here, we uncover an unexpected link between the transcription factor Zfp335 and control of cGAS/STING-dependent cell death in post-β-selection DN4 thymocytes. Zfp335 controls survival by sustaining expression of Ankle2, which suppresses cGAS/STING-dependent cell death. Together, this study identifies Zfp335 as a key transcription factor regulating the survival of proliferating post-β-selection thymocytes and demonstrates a key role for the cGAS/STING pathway in driving apoptosis of developing T cells.

Date: 2022
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DOI: 10.1038/s41467-022-33610-4

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