A co-stimulatory molecule on activated T cells, H4/ICOS, delivers specific signals in T_h cells and regulates their responses

We examined the co-stimulatory activity of H4/ICOS on murine activated CD4⁺ T cells and found that the cross-linking of H4/ICOS enhanced their proliferation, in addition to raising IFN-γ, IL-4 and IL-10 production to levels comparable to those induced by CD28. However, IL-2 production was only marginally co-stimulated by H4/ICOS. This distinct pattern of lymphokine production appears to be induced by a specific intracellular signaling event. Compared with CD28, H4/ICOS dominantly elicited the Akt pathway via phosphatidylinositol 3-kinase. In addition, mitogen-activated protein kinase family kinases were activated in different ways by CD28 and H4/ICOS. The strong phosphorylation of p46 c-Jun N-terminal kinase was observed upon CD28 co-stimulation, but was less potently induced by H4/ICOS. The strain diversity in the induction of H4/ICOS was recognized. The expression of H4/ICOS on BALB/c activated CD4⁺ T cells was >6-fold higher compared with C57BL/6 activated CD4⁺ T cells. Furthermore, BALB/c activated CD4⁺ T cells exhibited more T_h2-deviated lymphokine production as compared with C57BL/6 activated CD4⁺ T cells and signaling through H4/ICOS during the primary stimulation of naive CD4⁺ T cells promoted the generation of T_h2 cells. Thus, the difference in H4/ICOS expression on activated CD4⁺ T cells, which is regulated among the mouse strains, may also regulate the polarization of T_h cells.