The autoimmune suppressor Gadd45α inhibits the T cell alternative p38 activation pathway

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Abstract
The p38 MAP kinase (MAPK) is phosphorylated and activated by upstream MAPK kinases. T cells have an alternative pathway in which T cell receptor–activated tyrosine kinase Zap70 phosphorylates p38 on Tyr323. Mice lacking Gadd45α, a small p38-binding molecule, develop a lupus-like autoimmune disease. Here we show that resting T cells but not B cells from Gadd45a−/− mice had spontaneously increased p38 activity in the absence of 'upstream' MAPK kinase activation. The p38 from resting Gadd45a−/− T cells was spontaneously phosphorylated on Tyr323, and its activity was specifically inhibited by recombinant Gadd45α in vitro. Thus, constitutive activation of T cell p38 through the alternative pathway is prevented by Gadd45α, the absence of which results in p38 activation, T cell hyperproliferation and autoimmunity.