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

Abstract

Stimulation via the T-cell receptor (TCR) activates p38␣ and p38␤ by phosphorylation of p38 Tyr-323 (p38 Y323 ). Here we characterize knockin mice in which p38␣ and/or ␤ Tyr-323 has been replaced with Phe. We find that p38␣ accounts for twothirds and p38␤ the remainder of TCRinduced p38 activation. T cells from double knockin mice (p38␣␤ 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 p38␣ Y323F into Gadd45␣-deficient mice, in which the alternative p38 pathway is constitutively active, reversed T-cell hyperproliferation and autoimmunity. Furthermore, p38␣␤ 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 tissuespecific target for intervention in these processes. (Blood. 2011;118(12):3280-3289)

The Emerging Role of p38 Mitogen-Activated Protein Kinase in Multiple Sclerosis and Its Models

“…As mentioned above, an alternative activation pathway of p38 MAPK through autophosphorylation has been identified in T cells (18,19). Lack of this T cell-specific alternative activation pathway of p38 MAPK in knock-in mutant mice also resulted in impaired Th17 function that correlated with diminished EAE severity (35). These studies also indicate a direct effect of p38 MAPK signaling in T cells.…”

“…Using both pharmacologic inhibitors of p38 MAPK and different genetically manipulated mouse models, the activation of p38 MAPK has been shown to be required for the production of IL-17 by Th17 cells in vitro and in vivo (30)(31)(32)(33)(34)(35)(36). Regulation of STAT1 transcriptional activity has been proposed as a mechanism by which p38 MAPK regulates IFN-␥ transcription (27).…”

TAK1–JNK Axis Mediates Survival Signal through Mcl1 Stabilization in Activated T Cells

“…p38 MAPK has also been reported to have an essential role in IL-2 production and subsequent T cell proliferation (41,42). Therefore, it seems likely that the cytostatic effect of LL-Z1640-2 on TCR-induced T cell proliferation is attributed to the combined suppression of JNK and p38 MAPK signaling pathways.…”

Mechanism for p38α-mediated Experimental Autoimmune Encephalomyelitis

“…Recently, several groups reported a possible role of p38 in the pathogenesis of EAE as follows: a TLR-ASK1-p38 pathway in glial cells leads to chemokine release affecting leukocytic infiltration accompanied by severe EAE (30); activation of p38 in CD4 T cells contributes to EAE progression by controlling IL-17 production (32); p38␤ in concert with p38␣ participates in T cell receptor-mediated T cell proliferation, and its activity affects EAE progression (33). However, there is no evidence regarding a functional role of p38␣ in EAE.…”