The Emergence and Functional Fitness of Memory CD4+ T Cells Require the Transcription Factor Thpok

Author:

Ciucci, Thomas

Vacchio, Melanie S

Gao, Yayi

Tomassoni Ardori, Francesco

Candia, Julian

Mehta, Monika

Zhao, Yongmei

Tran, Bao

Pepper, Marion

Tessarollo, Lino

McGavern, Dorian B

Bosselut, Rémy
Author Address

Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA., Trans-NIH Center for Human Immunology, Autoimmunity, and Inflammation, National Institutes of Health, Bethesda, MD, USA., Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA., Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: remy.bosselut@nih.gov.,

Abstract:

Memory CD4+ T cells mediate long-term immunity, and their generation is a key objective of vaccination strategies. However, the transcriptional circuitry controlling the emergence of memory cells from early CD4+ antigen-responders remains poorly understood. Here, using single-cell RNA-seq to study the transcriptome of virus-specific CD4+ T cells, we identified a gene signature that distinguishes potential memory precursors from effector cells. We found that both that signature and the emergence of memory CD4+ T cells required the transcription factor Thpok. We further demonstrated that Thpok cell-intrinsically protected memory cells from a dysfunctional, effector-like transcriptional program, similar to but distinct from the exhaustion pattern of cells responding to chronic infection. Mechanistically, Thpok- bound genes encoding the transcription factors Blimp1 and Runx3 and acted by antagonizing their expression. Thus, a Thpok-dependent circuitry promotes both memory CD4+ T cells' differentiation and functional fitness, two previously unconnected critical attributes of adaptive immunity. Published by Elsevier Inc.

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