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Disruption of the p38aTyr323 alternative pathway prevents T cell receptor‐mediated p38aTyr323 activation in primary T cells
Author(s) -
Jirmanova Ludmila,
Sarma Dandapantula N.,
Jankovic Dragana,
Mittelstadt Paul,
Ashwell Jonathan D.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.391
Subject(s) - t cell receptor , p38 mitogen activated protein kinases , microbiology and biotechnology , t cell , biology , signal transduction , immune system , immunology , chemistry , mapk/erk pathway
T cells possess a p38 activation alternative pathway in which stimulation via the antigen receptor (TCR) induces phosphorylation of p38α and β on Tyr‐323. In resting T cells, Gadd45α, a small p38‐binding molecule, inhibits the activation of p38 by the T cell alternative pathway. Gadd45α‐deficient T cells display constitutively increased p38 activity, hyperproliferative response to TCR stimulation, and Gadd45α −/− mice develop an autoimmune diseases (AID). To assess the contribution of p38 alternative pathway to normal T cell function, we generated p38α "knock‐in" mice in which Tyr‐323 was replaced with Phe (p38α Y323F ). TCR‐mediated stimulation failed to activate p38α Y323F , as measured by p38α catalytic activity. Cell cycle entry was delayed in TCR‐stimulated p38α Y323F T cells, which also produced less IFN‐γ than wild type T cells in response to TCR‐mediated but not TCR‐independent stimuli. Following infection with Toxoplasma gondii tachyzoites, the p38α Y323F mice displayed higher counts of parasite cysts in brain and lower concentration of IFNγ in blood serum. Thus, the absence of the p38α alternative activation pathway impaired the immune response. To investigate the p38 role in development of autoimmune diseases Gadd45α knock‐out/p38α Y323F (G45KO/Y323F) mice were generated. The ongoing screening of antibodies against double strand DNA and histone will reveal the role of p38 alternative pathway in AID.