CD46/CD3 costimulation induces morphological changes of human T cells and activation of Vav, Rac, and extracellular signal-regulated kinase mitogen-activated protein kinase.
Efficient T cell activation requires at least two signals, one mediated by the engagement of the TCR-CD3 complex and another one mediated by a costimulatory molecule. We recently showed that CD46, a complement regulatory receptor for C3b as well as a receptor for several pathogens, could act as a potent costimulatory molecule for human T cells, highly promoting T cell proliferation. Indeed, we show in this study that CD46/CD3 costimulation induces a synergistic activation of extracellular signal-related kinase mitogen-activated protein kinase. Furthermore, whereas T lymphocytes primarily circulate within the bloodstream, activation may induce their migration toward secondary lymphoid organs or other tissues to encounter APCs or target cells. In this study, we show that CD46/CD3 costimulation also induces drastic morphological changes of primary human T cells, as well as actin relocalization. Moreover, we show that the GTP/GDP exchange factor Vav is phosphorylated upon CD46 stimulation alone, and that CD46/CD3 costimulation induces a synergistic increase of Vav phosphorylation. These results prompted us to investigate whether CD46/CD3 costimulation induced the activation of GTPases from the Rho family. Indeed, we report that the small GTPase Rac is also activated upon CD46/CD3 costimulation, whereas no change of Rho and Cdc42 activity could be detected. Therefore, CD46 costimulation profoundly affects T cell behavior, and these results provide important data concerning the biology of primary human T cells.
Zaffran
Y
Y
Institut National de la Santé et de la Recherche Médicale Unité 503, Centre Européen de Recherche en Virologie et Immunologie, Lyon, France.
Destaing
O
O
Roux
A
A
Ory
S
S
Nheu
T
T
Jurdic
P
P
Rabourdin-Combe
C
C
Astier
A L
AL
D000199:Actins / Q000032:analysis; D015703:Antigens, CD / Q000378:metabolism*; D017252:CD3 Complex / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000648:ultrastructure; D004789:Enzyme Activation; D006801:Humans; D007700:Kinetics; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000648:ultrastructure; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D000199:Actins; D015703:Antigens, CD; D017252:CD3 Complex; C497857:CD46 protein, human; D018797:Cell Cycle Proteins; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; C496618:VAV1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins