Src-family kinases negatively regulate NFAT signaling in resting human T cells

Alan Baer; Winston Colon-Moran; Jinhua Xiang; Jack T Stapleton; Nirjal Bhattarai

doi:10.1371/journal.pone.0187123

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Src-family kinases negatively regulate NFAT signaling in resting human T cells

Journal article

Open access

Peer reviewed

Src-family kinases negatively regulate NFAT signaling in resting human T cells

Alan Baer, Winston Colon-Moran, Jinhua Xiang, Jack T Stapleton and Nirjal Bhattarai

PloS one, Vol.12(10), pp.e0187123-e0187123

2017

DOI: 10.1371/journal.pone.0187123

PMCID: PMC5658144

PMID: 29073235

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Abstract

T cell signaling is required for activation of both natural and therapeutic T cells including chimeric antigen receptor (CAR) T cells. Identification of novel factors and pathways regulating T cell signaling may aid in development of effective T cell therapies. In resting human T cells, the majority of Src-family of tyrosine kinases (SFKs) are inactive due to phosphorylation of a conserved carboxy-terminal tyrosine residue. Recently, a pool of enzymatically active SFKs has been identified in resting T cells; however, the significance of these is incompletely understood. Here, we characterized the role of active SFKs in resting human T cells. Pharmacologic inhibition of active SFKs enhanced distal TCR signaling as measured by IL-2 release and CD25 surface expression following TCR-independent activation. Mechanistically, inhibition of the active pool of SFKs induced nuclear translocation of NFAT1, and enhanced NFAT1-dependent signaling in resting T cells. The negative regulation of NFAT1 signaling was in part mediated by the Src-kinase Lck as human T cells lacking Lck had increased levels of nuclear NFAT1 and demonstrated enhanced NFAT1-dependent gene expression. Inhibition of active SFKs in resting primary human T cells also increased nuclear NFAT1 and enhanced NFAT1-dependent signaling. Finally, the calcineurin inhibitor FK506 and Cyclosporin A reversed the effect of SFKs inhibition on NFAT1. Together, these data identified a novel role of SFKs in preventing aberrant NFAT1 activation in resting T cells, and suggest that maintaining this pool of active SFKs in therapeutic T cells may increase the efficacy of T cell therapies.

Calcineurin Inhibitors - pharmacology

Humans

Jurkat Cells

NFATC Transcription Factors - metabolism

Receptors, Antigen, T-Cell - metabolism

Signal Transduction

src-Family Kinases - metabolism

T-Lymphocytes - drug effects

T-Lymphocytes - metabolism

Details

Title: Subtitle: Src-family kinases negatively regulate NFAT signaling in resting human T cells
Creators: Alan Baer - Center for Biologics Evaluation and Research
Winston Colon-Moran - Center for Biologics Evaluation and Research
Jinhua Xiang - University of Iowa
Jack T Stapleton - University of Iowa
Nirjal Bhattarai - Center for Biologics Evaluation and Research
Resource Type: Journal article
Publication Details: PloS one, Vol.12(10), pp.e0187123-e0187123
DOI: 10.1371/journal.pone.0187123
PMID: 29073235
PMCID: PMC5658144
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Grant note: DOI: 10.13039/100000038, name: U.S. Food and Drug Administration
Language: English
Date published: 2017
Academic Unit: Microbiology and Immunology; Infectious Diseases; Internal Medicine
Record Identifier: 9984297431902771

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