Induction, binding specificity and function of human ICOS

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.