TI - The autoimmune suppressor Gadd45alpha inhibits the T cell alternative p38 activation pathway . AB - 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 Gadd45alpha , 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 Gadd45alpha in vitro . Thus , constitutive activation of T cell p38 through the alternative pathway is prevented by Gadd45alpha , the absence of which results in p38 activation , T cell hyperproliferation and autoimmunity .