alexa Genetic disruption of p38alpha Tyr323 phosphorylation prevents T-cell receptor-mediated p38alpha activation and impairs interferon-gamma production.


Journal of Clinical & Cellular Immunology

Author(s): Jirmanova L, Sarma DN, Jankovic D, Mittelstadt PR, Ashwell JD

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Abstract T cells possess a p38 activation alternative pathway in which stimulation via the antigen receptor (T-cell receptor [TCR]) induces phosphorylation of p38alpha and beta on Tyr323. To assess the contribution of this pathway to normal T-cell function, we generated p38alpha knockin mice in which Tyr323 was replaced with Phe (p38alpha(Y323F)). TCR-mediated stimulation failed to activate p38alpha(Y323F) as measured by phosphorylation of the Thr-Glu-Tyr activation motif and p38alpha catalytic activity. Cell-cycle entry was delayed in TCR-stimulated p38alpha(Y323F) T cells, which also produced less interferon (IFN)-gamma than wild-type T cells in response to TCR-mediated but not TCR-independent stimuli. p38alpha(Y323F) mice immunized with T-helper 1 (Th1)-inducing antigens generated normal Th1 effector cells, but these cells produced less IFN-gamma than wild-type cells when stimulated through the TCR. Thus, the Tyr323-dependent pathway and not the classic mitogen-activated protein (MAP) kinase cascade is the physiologic means of p38alpha activation through the TCR and is necessary for normal Th1 function but not Th1 generation.
This article was published in Blood and referenced in Journal of Clinical & Cellular Immunology

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