Induction, binding specificity and function of human ICOS

Abstract

Recently, we have identified the inducible co‐stimulator (ICOS), an activation‐dependent, T cell‐specific cell surface molecule related to CD28 and CTLA‐4. Detailed analysis of human ICOS presented here shows that it is a 55‐60‐kDa homodimer with differently N‐glycosylated subunits of 27 and 29 kDa. ICOS requires both phorbol 12‐myristate 13‐acetate and ionomycin for full induction, and is sensitive to Cyclosporin A. ICOS is up‐regulated early on all T cells, including the CD28– subset, and continues to be expressed into later phases of T cell activation. On stimulation of T cells by antigen‐presenting cells, the CD28/B7, but not the CD40 ligand/CD40 pathway is critically involved in the induction of ICOS. ICOS does not bind to B7‐1 or B7‐2, and CD28 does not bind to ICOS ligand; thus the CD28 and ICOS pathways do not cross‐interact on the cell surface. In vivo, ICOS is expressed in the medulla of the fetal and newborn thymus, in the T cell zones of tonsils and lymph nodes, and in the apical light zones of germinal centers (predominant expression). Functionally, ICOS co‐induces a variety of cytokines including IL‐4, IL‐5, IL‐6, IFN‐γ, TNF‐α, GM‐CSF, but not IL‐2, and superinduces IL‐10. Furthermore, ICOS co‐stimulation prevents the apoptosis of pre‐activated T cells. The human ICOS gene maps to chromosome 2q33 – 34.

ICOS-Induced B7h Shedding on B Cells Is Inhibited by TLR7/8 and TLR9

“…ICOS costimulation regulates production of multiple cytokines, including IL-4, IL-10, and IFN-␥ (1,4,10,11), and is critical in Ab responses to T-dependent Ags (11)(12)(13)(14)(15). ICOS costimulation regulates effector functions of both Th2 and Th1 cells (16), as well as CD8 ϩ T cells (17,18).…”

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

“…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).…”