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Alternative ZAP70-p38 signals prime a classical p38 pathway through LAT and SOS to support regulatory T cell
Jesse E Jun1, Kayla R Kulhanek1, Hang Chen2
1Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
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.
Insights
T cell activation involves classical and alternative p38 pathways. Basal ZAP70 primes classical p38, while Sos1/2 deletion impairs IL-2 production and regulatory T cell differentiation, impacting immune balance.
Area of Science:
- Immunology
- Cell Signaling
Background:
- T cell receptor (TCR) stimulation activates multiple kinase pathways, including mitogen-activated protein kinases (MAPKs), phosphoinositide 3-kinases (PI3Ks), and mTOR.
- p38 MAPK can be activated via a classical pathway involving LAT or an alternative pathway involving ZAP70.
Purpose of the Study:
- To investigate the distinct contributions of classical and alternative p38 pathways to T cell activation.
- To understand how ZAP70 and LAT signalosome components influence p38 activation and downstream T cell functions.
Main Methods:
- Dual-parameter phosphoflow cytometry to analyze intracellular signaling.
- In silico computation for pathway analysis.
- T cell-specific deletion of Sos1 and Sos2 in mice.
Main Results:
- Basal ZAP70 activation primes the classical p38 pathway, lowering the TCR stimulation threshold.
- T cell-specific deletion of Sos1 and Sos2 reduced classical p38 signaling.
- Sos1/2 deficiency led to impaired IL-2 production, reduced regulatory T cell differentiation, and exacerbated experimental autoimmune encephalomyelitis (EAE).
Conclusions:
- Both classical and alternative p38 pathways are crucial for maintaining immune homeostasis.
- The interplay between ZAP70, LAT, and p38 signaling regulates critical T cell functions and immune balance.
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