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Mechanisms of H4/ICOS costimulation: effects on proximal TCR signals and MAP kinase pathways
Author(s) -
Feito Maria Jose,
Vaschetto Rosanna,
Criado Gabriel,
Sánchez Alejandra,
Chiocchetti Annalisa,
JiménezPeriáñez Arturo,
Dianzani Umberto,
Portoles Pilar,
Rojo Jose M.
Publication year - 2003
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/immu.200390023
Subject(s) - biology , t cell receptor , microbiology and biotechnology , signal transduction , kinase , immunology , t cell , immune system
Abstract 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, ζ, 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 andIL‐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.