Induction, binding specificity and function of human ICOS
K C Beier1, A Hutloff, A M Dittrich
1Molecular Immunology, Robert Koch-Institute, Berlin, Germany.
Insights
Inducible co-stimulator (ICOS) is a T cell molecule crucial for immune responses. ICOS enhances cytokine production and prevents T cell death, playing a key role in immune regulation.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- The inducible co-stimulator (ICOS) is a T cell-specific surface molecule related to CD28 and CTLA-4.
- ICOS plays a role in T cell activation and immune responses.
Purpose of the Study:
- To characterize the human inducible co-stimulator (ICOS) molecule.
- To investigate the induction, function, and expression of ICOS in T cells.
Main Methods:
- Analysis of human ICOS protein structure and glycosylation.
- Investigation of ICOS induction by phorbol 12-myristate 13-acetate, ionomycin, and Cyclosporin A.
- Examination of ICOS expression during T cell activation and in various lymphoid tissues.
Main Results:
- Human ICOS is a 55-60 kDa homodimer with distinct subunits.
- ICOS is upregulated early in T cell activation, independent of the CD40 ligand/CD40 pathway but dependent on CD28/B7.
- ICOS co-stimulates various cytokines (IL-4, IL-5, IL-6, IFN-γ, TNF-α, GM-CSF, IL-10) and prevents T cell apoptosis.
Conclusions:
- ICOS is a critical co-stimulatory molecule involved in T cell activation, cytokine production, and survival.
- ICOS expression is regulated by T cell activation signals and found in specific immune microenvironments.
- The findings highlight ICOS as a potential therapeutic target in immune modulation.
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-gamma, TNF-alpha, 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.
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