LAUSR

“Alternative” ZAP70–dependent activation of the kinase p38 increases activation of the “classical” p38 cascade in T cells. Tipping the balance In T lymphocytes, the activity of the kinase p38 is required for the differentiation of both proinflammatory T cells and regulatory T cells. Antigen receptor stimulation activates p38 through a “classical” kinase cascade and through “alternative” ZAP70–dependent phosphorylation. Jun et al. found that after antigen receptor stimulation of model cell lines, strong p38 activation required activation of both p38 pathways. The experimental data fit a mathematical model in which initiation of the classical p38 cascade was augmented by basal alternative p38 activation. Loss of the guanine nucleotide exchange factor SOS1/2 inhibited classical but not alternative p38 activation, reduced regulatory T cell development, and exacerbated autoimmune disease in mice. These data suggest that p38 activation through distinct mechanisms may have different consequences on T cell function. 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.