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

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 Gadd45 alpha, 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 Gadd45a in vitro. Thus, constitutive activation of T cell p38 through the alternative pathway is prevented by Gadd45a, the absence of which results in p38 activation, T cell hyperproliferation and autoimmunity.