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Blood, 5 March 2009, Vol. 113, No. 10, pp. 2229-2237.
Prepublished online as a Blood First Edition Paper on November 14, 2008; DOI 10.1182/blood-2008-04-153304.
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IMMUNOBIOLOGY
Genetic disruption of p38 Tyr323 phosphorylation prevents T-cell receptor–mediated p38 activation and impairs interferon- production
Ludmila Jirmanova1,
Dandapantula N. Sarma1,
Dragana Jankovic2,
Paul R. Mittelstadt1, and
Jonathan D. Ashwell1
1 Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD; and
2 Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD
T cells possess a p38 activation alternative pathway in which stimulation via the antigen receptor (T-cell receptor [TCR]) induces phosphorylation of p38 and β on Tyr323. To assess the contribution of this pathway to normal T-cell function, we generated p38 knockin mice in which Tyr323 was replaced with Phe (p38Y323F). TCR-mediated stimulation failed to activate p38Y323F as measured by phosphorylation of the Thr-Glu-Tyr activation motif and p38 catalytic activity. Cell-cycle entry was delayed in TCR-stimulated p38Y323F T cells, which also produced less interferon (IFN)– than wild-type T cells in response to TCR-mediated but not TCR-independent stimuli. p38Y323F mice immunized with T-helper 1 (Th1)–inducing antigens generated normal Th1 effector cells, but these cells produced less IFN- 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 p38 activation through the TCR and is necessary for normal Th1 function but not Th1 generation.
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