Absence of the Adaptor Protein PEA-15 Is Associated with Altered Pattern of Th Cytokines Production by Activated CD4+ T Lymphocytes In Vitro, and Defective Red Blood Cell Alloimmune Response In Vivo

TCR-dependent and costimulation signaling, cell division, and cytokine environment are major factors driving cytokines expression induced by CD4(+) T cell activation. PEA-15 15 (Protein Enriched in Astrocyte / 15 kDa) is an adaptor protein that regulates death receptor-induced apoptosis and prolifer...

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Published inPloS one Vol. 10; no. 8; p. e0136885
Main Authors Kerbrat, Stéphane, Vingert, Benoit, Junier, Marie-Pierre, Castellano, Flavia, Renault-Mihara, François, Dos Reis Tavares, Silvina, Surenaud, Mathieu, Noizat-Pirenne, France, Boczkowski, Jorge, Guellaën, Georges, Chneiweiss, Hervé, Le Gouvello, Sabine
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 28.08.2015
Public Library of Science (PLoS)
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Summary:TCR-dependent and costimulation signaling, cell division, and cytokine environment are major factors driving cytokines expression induced by CD4(+) T cell activation. PEA-15 15 (Protein Enriched in Astrocyte / 15 kDa) is an adaptor protein that regulates death receptor-induced apoptosis and proliferation signaling by binding to FADD and relocating ERK1/2 to the cytosol, respectively. By using PEA-15-deficient mice, we examined the role of PEA-15 in TCR-dependent cytokine production in CD4(+) T cells. TCR-stimulated PEA-15-deficient CD4(+) T cells exhibited defective progression through the cell cycle associated with impaired expression of cyclin E and phosphoRb, two ERK1/2-dependent proteins of the cell cycle. Accordingly, expression of the division cycle-dependent cytokines IL-2 and IFNγ, a Th1 cytokine, was reduced in stimulated PEA-15-deficient CD4(+) T cells. This was associated with abnormal subcellular compartmentalization of activated ERK1/2 in PEA-15-deficient T cells. Furthermore, in vitro TCR-dependent differentiation of naive CD4(+) CD62L(+) PEA-15-deficient T cells was associated with a lower production of the Th2 cytokine, IL-4, whereas expression of the Th17-associated molecule IL4I1 was enhanced. Finally, a defective humoral response was shown in PEA-15-deficient mice in a model of red blood cell alloimmunization performed with Poly IC, a classical adjuvant of Th1 response in vivo. Collectively, our data suggest that PEA-15 contributes to the specification of the cytokine pattern of activated Th cells, thus highlighting a potential new target to interfere with T cell functional polarization and subsequent immune response.
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Competing Interests: The authors have declared that no competing interest exist.
Conceived and designed the experiments: BV MPJ FC JB GG HC SLG. Performed the experiments: SK BV FC FRM SDRT MS. Analyzed the data: SK BV MPJ FC SDRT MS JB GG HC SLG. Contributed reagents/materials/analysis tools: BV MPJ FC FNP. Wrote the paper: SK BV MPJ FC GG HC SLG.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0136885