Mechanisms of H4/ICOS costimulation: effects on proximal TCR signals and MAP kinase pathways.
H4/ICOS is a costimulatory molecule related to CD28. Its effects on early TCR signals have been analyzed in mouse CD4(+) Th2 cells, expressing H4/ICOS at higher levels than Th1 clones. Anti-H4/ICOS antibodies strongly enhanced CD3-mediated tyrosine phosphorylation of ZAP-70, zeta, or Vav, as well as extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 MAP kinase activation in these cells. The association of phosphoinositide 3-kinase (PI-3K) to H4/ICOS was enhanced by H4/ICOS cross-linking, and PI-3K inhibitors inhibited ERK and JNK activation and IL-4/IL-10 secretion, but not p38 MAP kinase or ZAP-70 activation. H4/ICOS-mediated activation of JNK, but not ERK or p38, is partially dependent on the expression of CD4 by the cells, whereas H4/ICOS costimulation is partially independent on CD28 expression. Cytochalasin D, an inhibitor of actin polymerization, inhibited ZAP-70, MAP kinase activation, or IL-4/IL-10 secretion. Neither cyclosporin A nor inhibitors of PKC produced detectable inhibition of ZAP-70 phosphorylation or MAP kinase activation in these Th2 cells. Cyclosporin A strongly inhibited IL-4, but not IL-10 secretion. ERK or JNKinhibitors partially inhibited IL-4 and IL-10 secretion, while PKC or p38 inhibitors had no significant effects on IL-4 or IL-10 secretion. Taken together, our data show clear similarities of costimulation mechanisms between H4/ICOS and CD28 during the early steps of TCR activation.
Feito
Maria Jose
MJ
Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.
Vaschetto
Rosanna
R
Criado
Gabriel
G
Sánchez
Alejandra
A
Chiocchetti
Annalisa
A
Jiménez-Periáñez
Arturo
A
Dianzani
Umberto
U
Portoles
Pilar
P
Rojo
Jose M
JM
D000199:Actins / Q000378:metabolism; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D017252:CD3 Complex / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D002460:Cell Line; D003599:Cytoskeleton / Q000378:metabolism; D060889:Inducible T-Cell Co-Stimulator Protein; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D018417:Th1 Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism
D000199:Actins; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D011948:Receptors, Antigen, T-Cell; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D019703:Calcineurin