RRC ID 67104
著者 Jun JE, Kulhanek KR, Chen H, Chakraborty A, Roose JP.
タイトル Alternative ZAP70-p38 signals prime a classical p38 pathway through LAT and SOS to support regulatory T cell differentiation.
ジャーナル Sci Signal
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.
巻・号 12(591)
公開日 2019-7-23
DOI 10.1126/scisignal.aao0736
PII 12/591/eaao0736
PMID 31337738
PMC PMC7340343
MeSH 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*
IF 6.467
リソース情報
ヒト・動物細胞 Sos1^(-)/Sos2^(-)DT40(RCB1868)