Crry/p65, a membrane complement regulatory protein, has costimulatory properties on mouse T cells.
It is known that certain type I membrane molecules (complement receptors type 1 and 2) belonging to the regulators of complement activation (RCA) family are involved in the regulation of B lymphocyte activation. In contrast, only GPI-anchored RCA molecules (CD55) have been described to be involved in T lymphocyte activation. In this study, we describe a novel function for the mouse RCA type I membrane protein Crry/p65 as a costimulatory molecule in CD4+ T cell activation. This is shown by increased anti-CD3-induced proliferation of CD4+ spleen T lymphocytes in the presence of the Crry/p65-specific mAb P3D2. Furthermore, Ab-induced coligation of Crry/p65 and CD3 favors IL-4 rather than IFN-gamma secretion in these cells. Crry/p65 signaling was also observed regardless of additional Ca2+, protein kinase C, or CD28-mediated costimuli. Analysis of intracellular intermediaries shows that Crry/p65-CD3 coligation enhances certain TCR/CD3-mediated signals, producing increased early tyrosine phosphorylation of many substrates and enhanced activation of the mitogen-activated protein kinase, extracellular signal-related kinase. These data fit well with the association of Crry/p65 with the tyrosine kinase Lck found in T cell lysates. The epitope recognized by the mAb P3D2 interferes with the protective role of Crry/p65 on C3 deposition. The relationship between protective function and costimulation by Crry/p65 is discussed. Our results support a multifunctional role for Crry/p65 in T cells and suggest new links between the natural and adaptive immune responses.
Fernández-Centeno
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E
Centro Nacional de Biología Fundamental, Instituto de Salud Carlos III, Madrid, Spain.
de Ojeda
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G
Rojo
J M
JM
Portolés
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P
D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000954:Antigens, Surface; D001666:Binding Sites, Antibody; D017252:CD3 Complex / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000276:immunology; D005260:Female; D006801:Humans; D020014:K562 Cells; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D051381:Rats; D011917:Rats, Inbred Lew; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology; D011956:Receptors, Cell Surface; D011951:Receptors, Complement / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D017463:Receptors, Complement 3b; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D017252:CD3 Complex; C081470:Cr1l protein, mouse; C513105:Cr1l protein, rat; D008024:Ligands; D008222:Lymphokines; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011956:Receptors, Cell Surface; D011951:Receptors, Complement; D017463:Receptors, Complement 3b