Regulation of mouse inducible costimulator (ICOS) expression by Fyn-NFATc2 and ERK signaling in T cells.

The inducible costimulator (ICOS), a member of the CD28 family of costimulatory molecules, is rapidly induced upon T cell activation. Although the critical role of ICOS in costimulating T cell responses is well documented, little is known of the intracellular signaling pathways and mechanisms that regulate ICOS expression. Here, we report that Fyn, NFAT, and ERK signaling influence ICOS expression as various chemical inhibitors, such as PP2 that targets Src kinases, U0126 that targets MEK1/2, and cyclosporin A or FK506 that targets calcineurin and thereby affects NFAT, attenuate T cell receptor-mediated ICOS induction. Moreover, ectopic expression of NFATc2 or a constitutively active MEK2 amplifies ICOS transcription and transactivates a 288-bp core region of the icos promoter in luciferase reporter assays. We also identify a site on the icos promoter that is sensitive to ERK signaling and further show that NFATc2 can bind the icos promoter in vivo and that this binding is diminished when Fyn signaling is ablated. The normal activation of ERK but reduced nuclear translocation of NFATc2 in Fyn(-/-) CD4(+) T cells further suggest that Fyn and NFATc2 act in a common axis, separate from that involving ERK, to drive ICOS transcription. Taken together, our findings indicate that Fyn-calcineurin-NFATc2 and MEK2-ERK1/2 are two independent signaling pathways that cooperate to control T cell receptor-mediated ICOS induction.