Alternative ZAP70-p38 signals prime a classical p38 pathway through LAT and SOS to support regulatory T cell differentiation

Jesse E. Jun, Kayla R. Kulhanek, Hang Chen, Arup Chakraborty, Jeroen P. Roose

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

T cell receptor (TCR) stimulation activates diverse kinase pathways, which include the mitogen-activated protein kinases (MAPKs) ERK and p38, the phosphoinositide 3-kinases (PI3Ks), and the kinase mTOR. Although TCR stimulation activates the p38 pathway through a "classical" MAPK cascade that is mediated by the adaptor protein LAT, it also stimulates an "alternative" pathway in which p38 is activated by the kinase ZAP70. Here, we used dual-parameter, phosphoflow cytometry and in silico computation to investigate how both classical and alternative p38 pathways contribute to T cell activation. We found that basal ZAP70 activation in resting T cell lines reduced the threshold ("primed") TCR-stimulated activation of the classical p38 pathway. Classical p38 signals were reduced after T cell- specific deletion of the guanine nucleotide exchange factors Sos1 and Sos2, which are essential LAT signalosome components. As a consequence of Sos1/2 deficiency, production of the cytokine IL-2 was impaired, differentiation into regulatory T cells was reduced, and the autoimmune disease EAE was exacerbated in mice. These data suggest that the classical and alternative p38 activation pathways exist to generate immune balance.

Original languageEnglish
Article numbereaao0736
JournalScience Signaling
Volume12
Issue number591
DOIs
StatePublished - 23 Jul 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2019 The Authors.

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