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Immunity. 2019 Jan 15;50(1):91-105.e4. doi: 10.1016/j.immuni.2018.12.019. Epub 2019 Jan 9.

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

Author information

1
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
2
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
3
Trans-NIH Center for Human Immunology, Autoimmunity, and Inflammation, National Institutes of Health, Bethesda, MD, USA.
4
Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
5
Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA.
6
Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
7
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.

KEYWORDS:

CD4 T cell; LCMV; T cell dysfunction; T cell memory; Thpok; immune response; single-cell RNA-seq; transcription factor

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