Lack of the T cell-specific alternative p38 activation pathway reduces autoimmunity and inflammation.

摘要

Stimulation via the T-cell receptor (TCR) activates p38alpha and p38beta by phosphorylation of p38 Tyr-323 (p38(Y323)). Here we characterize knockin mice in which p38alpha and/or beta Tyr-323 has been replaced with Phe. We find that p38alpha accounts for two-thirds and p38beta the remainder of TCR-induced p38 activation. T cells from double knockin mice (p38alphabeta(Y323F)) had defects in TCR-mediated proliferation and Th1 and Th17 skewing, the former corresponding with an inability to sustain T-bet expression. Introduction of p38alpha(Y323F) into Gadd45alpha-deficient mice, in which the alternative p38 pathway is constitutively active, reversed T-cell hyperproliferation and autoimmunity. Furthermore, p38alphabeta(Y323F) mice had delayed onset and reduced severity of the inflammatory autoimmune diseases collagen-induced arthritis and experimental autoimmune encephalomyelitis. Thus, T cell-specific alternative activation of p38 is an important pathway in T-cell proliferation, Th skewing, and inflammatory autoimmunity, and may be an attractive tissue-specific target for intervention in these processes.