title: 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.
abstract: 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.
authors: Université Paris-Est, Créteil, France; Inserm U955, Créteil, France.
authors: Stéphane
authors: S
authors: Kerbrat
authors: Inserm U955, Créteil, France; Etablissement Français du Sang, Créteil, France.
authors: Benoit
authors: B
authors: Vingert
authors: Inserm, U1130, Neuroscience Paris Seine, IBPS, Paris, France; Université Pierre et Marie Curie, UM119, Neuroscience Paris Seine, IBPS, Paris, France; CNRS, UMR8246, Neuroscience Paris Seine, IBPS, Paris, France.
authors: Marie-Pierre
authors: MP
authors: Junier
authors: Université Paris-Est, Créteil, France; Inserm U955, Créteil, France; AP-HP, Hôpital H. Mondor- A. Chenevier, Pôle de Biologie-Pathologie, Créteil, France.
authors: Flavia
authors: F
authors: Castellano
authors: Inserm, U1130, Neuroscience Paris Seine, IBPS, Paris, France; Université Pierre et Marie Curie, UM119, Neuroscience Paris Seine, IBPS, Paris, France; CNRS, UMR8246, Neuroscience Paris Seine, IBPS, Paris, France.
authors: François
authors: F
authors: Renault-Mihara
authors: Inserm, U1130, Neuroscience Paris Seine, IBPS, Paris, France; Université Pierre et Marie Curie, UM119, Neuroscience Paris Seine, IBPS, Paris, France; CNRS, UMR8246, Neuroscience Paris Seine, IBPS, Paris, France.
authors: Silvina
authors: S
authors: Dos Reis Tavares
authors: Inserm U955, Créteil, France.
authors: Mathieu
authors: M
authors: Surenaud
authors: Université Paris-Est, Créteil, France; Inserm U955, Créteil, France; Etablissement Français du Sang, Créteil, France.
authors: France
authors: F
authors: Noizat-Pirenne
authors: Université Paris-Est, Créteil, France; Inserm U955, Créteil, France.
authors: Jorge
authors: J
authors: Boczkowski
authors: Université Paris-Est, Créteil, France; Inserm U955, Créteil, France.
authors: Georges
authors: G
authors: Guellaën
authors: Inserm, U1130, Neuroscience Paris Seine, IBPS, Paris, France; Université Pierre et Marie Curie, UM119, Neuroscience Paris Seine, IBPS, Paris, France; CNRS, UMR8246, Neuroscience Paris Seine, IBPS, Paris, France.
authors: Hervé
authors: H
authors: Chneiweiss
authors: Université Paris-Est, Créteil, France; Inserm U955, Créteil, France; AP-HP, Hôpital H. Mondor- A. Chenevier, Pôle de Biologie-Pathologie, Créteil, France.
authors: Sabine
authors: S
authors: Le Gouvello
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001803:Blood Transfusion; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D007116:Immunization, Passive; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000276:immunology*; D020935:MAP Kinase Signaling System; D051379:Mice; D010750:Phosphoproteins / Q000172:deficiency*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; C490444:Pea15 protein, mouse; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell