Genetic disruption of p38alpha Tyr323 phosphorylation prevents T-cell receptor-mediated p38alpha activation and impairs interferon-gamma production.
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.
Jirmanova
Ludmila
L
Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Sarma
Dandapantula N
DN
Jankovic
Dragana
D
Mittelstadt
Paul R
PR
Ashwell
Jonathan D
JD
D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D007371:Interferon-gamma / Q000096:biosynthesis*; D007527:Isoenzymes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D007527:Isoenzymes; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases