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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation
  • Chickens
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Enzyme Activation
  • Female
  • Flow Cytometry
  • Humans
  • Interleukin-2 / metabolism
  • Jurkat Cells
  • Kinetics
  • Leukocytes, Mononuclear / metabolism
  • Mice
  • Mice, Knockout
  • Protein Binding
  • Receptors, Antigen, T-Cell / metabolism
  • SOS1 Protein / metabolism
  • Son of Sevenless Proteins / metabolism
  • Stochastic Processes
  • T-Lymphocytes / cytology*
  • Th1 Cells / cytology
  • Th2 Cells / cytology
  • ZAP-70 Protein-Tyrosine Kinase / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Interleukin-2
  • Receptors, Antigen, T-Cell
  • SOS1 Protein
  • SOS1 protein, human
  • SOS2 protein, human
  • Son of Sevenless Proteins
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human
  • p38 Mitogen-Activated Protein Kinases