ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28

Abstract

The T-cell-specific cell-surface receptors CD28 and CTLA-4 are important regulators of the immune system. CD28 potently enhances those T-cell functions that are essential for an effective antigen-specific immune response, and the homologous CTLA-4 counterbalances the CD28-mediated signals and thus prevents an otherwise fatal overstimulation of the lymphoid system. Here we report the identification of a third member of this family of molecules, inducible co-stimulator (ICOS), which is a homodimeric protein of relative molecular mass 55,000-60,000 (M(r) 55K-60K). Matching CD28 in potency, ICOS enhances all basic T-cell responses to a foreign antigen, namely proliferation, secretion of lymphokines, upregulation of molecules that mediate cell-cell interaction, and effective help for antibody secretion by B cells. Unlike the constitutively expressed CD28, ICOS has to be de novo induced on the T-cell surface, does not upregulate the production of interleukin-2, but superinduces the synthesis of interleukin-10, a B-cell-differentiation factor. In vivo, ICOS is highly expressed on tonsillar T cells, which are closely associated with B cells in the apical light zone of germinal centres, the site of terminal B-cell maturation. Our results indicate that ICOS is another major regulator of the adaptive immune system.

ICOS-ligand, expressed on human endothelial cells, costimulates Th1 and Th2 cytokine secretion by memory CD4+T cells

“…Triggering of ICOS by ICOS-L expressed by EC had a profound effect on the secretion of Th1 as well as Th2 cytokines, a finding that corroborates the hypothesis that ICOS͞ICOS-L does not only have a role in the control of Th2, but might also have a critical function in the control of Th1 immune responses (38). On the basis of previous data, we and others suggested a model in which CD28 costimulates primary T cell functions, whereas ICOS plays a more prominent role in the costimulation of effector or memory T cell responses (10,39). Our functional data presented here are in agreement with such a concept.…”

“…8 and 9). Instead, ICOS-L binds to ICOS, a T cell-specific costimulatory molecule homologous to CD28 and CTLA-4 (8)(9)(10). The strong impact of ICOS͞ICOS-L interaction on T cell-mediated immune responses in vivo became evident by the disruption of the ICOS gene in mice.…”

Inducible costimulator-dependent IL-10 production by regulatory T cells specific for self-antigen

“…It has been suggested that stimulation of ICOS on CD4 ϩ T cells preferentially promotes IL-10 production (23,32,33). Moreover, the importance of the ICOS molecule in IL-10-producing Tr cells was reported in respiratory tolerance (25).…”

“…A new member of the CD28 family, inducible costimulator (ICOS) is a T cell-specific cell-surface molecule structurally related to CD28 and cytotoxic T lymphocyte-associated antigen 4 (23,24). Both CD28 and ICOS molecules are able to amplify the secretion of several cytokines, but only CD28 induces substantial amounts of IL-2, whereas ICOS shows a certain preference for the induction of IL-10 (23).…”

Akt Is a Neutral Amplifier for Th Cell Differentiation

“…Current models suggest that greater CD28 signal can achieve Th2 differentiation (6,7). An inducible costimulator, ICOS, also called H4 (8,9) or AILIM (10), is a member of the CD28 family and has roles similar to those of CD28 except for IL-2 production (11)(12)(13). Accumulating evidence indicates a predominant role of ICOS in Th2-type immune responses, as exemplified by its promoting effect on Th2 cell differentiation, concomitant cytokine secretion, airway hypersensitivity reaction, and Igclass switching (14 -17).…”