Complement regulatory protein Crry/p65-mediated signaling in T lymphocytes: role of its cytoplasmic domain and partitioning into lipid rafts

Journal of Leukocyte Biology

Pilar Portolés¹  Arturo Jiménez-Periañez¹  Gloria Ojeda¹  Alejandra Sánchez⁴  Joaquín Madrenas³  Eliana Pini¹  Jose Maria Rojo⁴  Gabriel Criado² 

[1] Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain; Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain; Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain;;Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain; Robarts Research Institute and Departments of Microbiology and Immunology and Medicine, The University of Western Ontario, London, Canada; and Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain; Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain; Robarts Research Institute and Departments of Microbiology and Immunology and Medicine, The University of Western Ontario, London, Canada; and Robarts Research Institute and Departments of Microbiology and Immunology and Medicine, The University of Western Ontario, London, Canada; and Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain; Robarts Research Institute and Departments of Microbiology and Immunology and Medicine, The University of Western Ontario, London, Canada; and;Robarts Research Institute and Departments of Microbiology and Immunology and Medicine, The University of Western Ontario, London, Canada; and Robarts Research Institute and Departments of Microbiology and Immunology and Medicine, The University of Western Ontario, London, Canada; and Robarts Research Institute and Departments of Microbiology and Immunology and Medicine, The University of Western Ontario, London, Canada; and;Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain

关键词: costimulation;    cell surface molecule;    signal transduction;   

DOI  :  10.1189/jlb.1104642

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Crry/p65 is a type I glycoprotein, which protects mouse T cells from complement attack. We have previously shown that complement receptor I-related protein Crry/p65 (Crry) ligation has a costimulatory effect on mouse CD4+ T cell activation. Here, we have examined the mechanisms responsible for Crry costimulation, addressing the question of whether Crry potentiates signal transduction starting at the T cell receptor (TCR)/CD3 complex or promotes distinct costimulatory signals. We show that Crry increases early TCR-dependent activation signals, including p56lck-, ζ-associated protein-70 (ZAP-70), Vav-1, Akt, and extracellular signal-regulated kinase (ERK) phosphorylation but also costimulation-dependent mitogen-activated protein kinases (MAPK), such as the stress-activated c-Jun N-terminal kinase (JNK). It is intriguing that Crry costimulus enhanced p38 MAPK activation in T helper cell type 1 (Th1) but not in Th2 cells. A fraction of Crry is found consistently in the detergent-insoluble membrane fraction of Th1 or Th2 cells or CD4+ lymphoblasts. Crry costimulation induced clustering of lipid rafts, increasing their content in Crry, CD3ε, and p59-60 forms of p56lck, and caused actin polymerization close to the site of activation in Th2 cells. Such events were inhibited by wortmannin, suggesting a role for phosphatidylinositol-3 kinase in these effects. The Crry cytoplasmic domain was required for JNK activation and interleukin-4 secretion but not for the presence of Crry in rafts or activation of p56lck, ZAP-70, Akt, Vav-1, or ERK. This suggests that Crry costimulation involves two different but not mutually exclusive signal transduction modules. The dual function of Crry as a complement regulatory protein and as a T cell costimulator illustrates the importance of complement regulatory proteins as links between innate and adaptive immunity.

【 授权许可】

Unknown