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Sci Signal. 2019 Jul 23;12(591). pii: eaao0736. doi: 10.1126/scisignal.aao0736.

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

Author information

1
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
2
Departments of Chemical Engineering, Chemistry, and Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
3
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA. jeroen.roose@ucsf.edu.

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.

PMID:
31337738
DOI:
10.1126/scisignal.aao0736

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