A distinct role for ICOS-mediated co-stimulatory signaling in

While the ligand of inducible co-stimulator (ICOS), B7 homologus protein, is widely expressed in somatic cells, B7-1 and B7-2 expression is mainly limited to lymphoid organs. Thus, the activation of T cells through ICOS without a CD28-mediated signal may occur in physiological situations. In order to gain a better understanding of the role of the ICOS co-stimulatory signal in immune responses, we studied the cellular response of T cells to beads coated with anti-ICOS or anti-CD28, plus sub-optimal anti-CD3 mAb. We demonstrate that while CD28 ligation induced expansion of both CD41 and CD81 populations, ICOS ligation only resulted in the expansion of CD81 T cells, and induced apoptosis in the CD41 T cell population. It was found that IL-2 is critically required for CD81 T cell expansion triggered by ICOS ligation, whereas it had only a limited effect on the expansion of CD41 T cells. This distinct reactivity of CD41 and CD81 T cell populations to exogenous IL-2 strongly correlates with the expression level of IL-2 receptor b-chain, CD122, on T cells. Furthermore, we defined a small but distinct population of memory phenotype CD41 T cells that constitutively express ICOS. Interestingly, while naive CD41 T cells were unable to produce IL-2, ICOS-expressing T cells produced a substantial amount of IL-2 by stimulation with anti-ICOS/CD3 beads, suggesting that IL-2, which is indispensable for CD81 T cell expansion, is produced by this ICOS-expressing T cell population. These results provide evidence indicating that the ICOS co-stimulatory signal plays a distinct role in the development of CD41 and CD81 T cell-mediated immune responses