title: Lack of the T cell-specific alternative p38 activation pathway reduces autoimmunity and inflammation.
abstract: Stimulation via the T-cell receptor (TCR) activates p38α and p38β by phosphorylation of p38 Tyr-323 (p38(Y323)). Here we characterize knockin mice in which p38α and/or β Tyr-323 has been replaced with Phe. We find that p38α accounts for two-thirds and p38β the remainder of TCR-induced p38 activation. T cells from double knockin mice (p38αβ(Y323F)) had defects in TCR-mediated proliferation and Th1 and Th17 skewing, the former corresponding with an inability to sustain T-bet expression. Introduction of p38α(Y323F) into Gadd45α-deficient mice, in which the alternative p38 pathway is constitutively active, reversed T-cell hyperproliferation and autoimmunity. Furthermore, p38αβ(Y323F) mice had delayed onset and reduced severity of the inflammatory autoimmune diseases collagen-induced arthritis and experimental autoimmune encephalomyelitis. Thus, T cell-specific alternative activation of p38 is an important pathway in T-cell proliferation, Th skewing, and inflammatory autoimmunity, and may be an attractive tissue-specific target for intervention in these processes.
authors.affiliation: Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Jirmanova
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Giardino Torchia
authors.forename: Nandakumara D
authors.initials: ND
authors.lastname: Sarma
authors.forename: Paul R
authors.initials: PR
authors.lastname: Mittelstadt
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ashwell
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015551:Autoimmunity; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D049109:Cell Proliferation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D055879:Gene Knock-In Techniques; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D010649:Phenylalanine / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D014443:Tyrosine / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D010649:Phenylalanine; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D048051:p38 Mitogen-Activated Protein Kinases; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins