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Gene Review

ICOS  -  inducible T-cell co-stimulator

Homo sapiens

Synonyms: AILIM, Activation-inducible lymphocyte immunomediatory molecule, CD278, CVID1, Inducible T-cell costimulator
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Disease relevance of ICOS


Psychiatry related information on ICOS


High impact information on ICOS

  • 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 [6].
  • 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 [6].
  • Our results indicate that ICOS is another major regulator of the adaptive immune system [6].
  • T-cell co-stimulation through B7RP-1 and ICOS [7].
  • The phenotype of human ICOS deficiency, which differs in key aspects from that of the ICOS-/- mouse, suggests a critical involvement of ICOS in T cell help for late B cell differentiation, class-switching and memory B cell generation [3].

Chemical compound and disease context of ICOS

  • Melanotan II (PNU-83757; Pharmacia and Upjohn Inc) and IC-351 (Icos Corp) are new compounds for the treatment of erectile dysfunction (ED), and more light is shed on a role for apomorphine for the same indication [8].

Biological context of ICOS


Anatomical context of ICOS

  • 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) [11].
  • These data suggest that ICOS favors differentiation of Th effector cells when cooperates with appropriate activation stimuli such as CD3+CD28 or CD3+IL-2, whereas it supports differentiation of regulatory T cells when costimulatory signals are insufficient [12].
  • Eminent role of ICOS costimulation for T cells interacting with plasmacytoid dendritic cells [13].
  • In general, our data demonstrate an eminent role of ICOS in the interaction of T cells with PDC, and thus modify the current paradigm of CD28 dominance for the costimulation of T cells interacting with professional antigen-presenting cells [13].
  • METHODS: The levels of H4/ICOS expression on T cells among peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) from 28 patients with RA were analyzed by flow cytometry [14].

Associations of ICOS with chemical compounds

  • ICOS requires both phorbol 12-myristate 13-acetate and ionomycin for full induction, and is sensitive to Cyclosporin A [11].
  • Inducible costimulator (ICOS) ligand (ICOSL), a B7-related transmembrane glycoprotein with extracellular IgV and IgC domains, binds to ICOS on activated T cells and delivers a positive costimulatory signal for optimal T cell function [15].
  • AILIM/ICOS signaling induces the activation of phosphoinositide-3 (PI3)-kinase, the product of which, phosphatidylinositol 3,4,5-trisphosphate (PIP3), was found to be localized in the lamellipodia at the front part of the cells [16].
  • The mRNA for perforin was increased in sIBM (28.1 +/- 8.7) compared with controls (4.3 +/- 11.2, P = 0.18), and significantly correlated with mRNA of ICOS, ICOS-L and the degree of endomysial inflammation as assessed in coded haematoxylin/eosin tissue sections [17].
  • Amgen redux: ICOS Corporation [18].

Regulatory relationships of ICOS

  • Expression and function of the co-stimulator H4/ICOS on activated T cells of patients with rheumatoid arthritis [14].
  • To explore the role of H4/ICOS function in the inflammation of rheumatoid joints, lymphokine production by SF CD4+ T cells co-stimulated by H4/ICOS was assayed [14].
  • These data raise the interesting possibility that the signaling cascades between T-cell proliferation and IL-10 production are regulated by different molecules in AILIM/ICOS- and CD28-costimulated T-cells [19].
  • Using magnetic beads coated with anti-CD3 and varying amounts of anti-ICOS and anti-CTLA-4 Abs, we show that CTLA-4 ligation blocks ICOS costimulation [20].
  • Prior exposure of B7h-expressing APCs to ICOS-expressing cells inhibits their subsequent ability to costimulate IFN-gamma and IL-4 production from CD4+ T cells [21].

Other interactions of ICOS

  • The numbers of AILIM/ICOS-positive cells among human peripheral blood mononuclear cells (PBMC), and rat and mouse splenocytes were very low (0.5, 0.4, and 1.2%, respectively), and the cells included many CD4-positive T cells except in the case of rat [22].
  • We constructed a soluble-Ig fusion protein of the extracellular domain of human ICOS and used it as a probe to characterize expression patterns of the ICOS ligand (ICOSL) [23].
  • 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 [11].
  • Glomerular infiltration by CXCR3+ ICOS+ activated T cells in chronic allograft nephropathy with transplant glomerulopathy [24].
  • Thus, low to marginal IL-2 levels produced upon ICOS costimulation account for the greater sensitivity of this pathway to PD-1-mediated inhibition [25].

Analytical, diagnostic and therapeutic context of ICOS


  1. Evidence for unique association signals in SLE at the CD28-CTLA4-ICOS locus in a family-based study. Graham, D.S., Wong, A.K., McHugh, N.J., Whittaker, J.C., Vyse, T.J. Hum. Mol. Genet. (2006) [Pubmed]
  2. The diabetes susceptibility locus Idd5.1 on mouse chromosome 1 regulates ICOS expression and modulates murine experimental autoimmune encephalomyelitis. Greve, B., Vijayakrishnan, L., Kubal, A., Sobel, R.A., Peterson, L.B., Wicker, L.S., Kuchroo, V.K. J. Immunol. (2004) [Pubmed]
  3. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Grimbacher, B., Hutloff, A., Schlesier, M., Glocker, E., Warnatz, K., Dräger, R., Eibel, H., Fischer, B., Schäffer, A.A., Mages, H.W., Kroczek, R.A., Peter, H.H. Nat. Immunol. (2003) [Pubmed]
  4. Hyperexpression of inducible costimulator and its contribution on lamina propria T cells in inflammatory bowel disease. Sato, T., Kanai, T., Watanabe, M., Sakuraba, A., Okamoto, S., Nakai, T., Okazawa, A., Inoue, N., Totsuka, T., Yamazaki, M., Kroczek, R.A., Fukushima, T., Ishii, H., Hibi, T. Gastroenterology (2004) [Pubmed]
  5. Tadalafil, a further innovation in the treatment of sexual dysfunction. Pomerol, J.M., Rabasseda, X. Drugs of today (Barcelona, Spain : 1998) (2003) [Pubmed]
  6. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Hutloff, A., Dittrich, A.M., Beier, K.C., Eljaschewitsch, B., Kraft, R., Anagnostopoulos, I., Kroczek, R.A. Nature (1999) [Pubmed]
  7. T-cell co-stimulation through B7RP-1 and ICOS. Yoshinaga, S.K., Whoriskey, J.S., Khare, S.D., Sarmiento, U., Guo, J., Horan, T., Shih, G., Zhang, M., Coccia, M.A., Kohno, T., Tafuri-Bladt, A., Brankow, D., Campbell, P., Chang, D., Chiu, L., Dai, T., Duncan, G., Elliott, G.S., Hui, A., McCabe, S.M., Scully, S., Shahinian, A., Shaklee, C.L., Van, G., Mak, T.W., Senaldi, G. Nature (1999) [Pubmed]
  8. American Urological Association--94th annual meeting. 1-6 May 1999, Dallas, USA. Adeniyi, A. IDrugs : the investigational drugs journal. (1999) [Pubmed]
  9. Signatures of strong population differentiation shape extended haplotypes across the human CD28, CTLA4, and ICOS costimulatory genes. Butty, V., Roy, M., Sabeti, P., Besse, W., Benoist, C., Mathis, D. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  10. Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. Riley, J.L., Mao, M., Kobayashi, S., Biery, M., Burchard, J., Cavet, G., Gregson, B.P., June, C.H., Linsley, P.S. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  11. Induction, binding specificity and function of human ICOS. Beier, K.C., Hutloff, A., Dittrich, A.M., Heuck, C., Rauch, A., Büchner, K., Ludewig, B., Ochs, H.D., Mages, H.W., Kroczek, R.A. Eur. J. Immunol. (2000) [Pubmed]
  12. ICOS cooperates with CD28, IL-2, and IFN-gamma and modulates activation of human na??ve CD4(+) T cells. Mesturini, R., Nicola, S., Chiocchetti, A., Bernardone, I.S., Castelli, L., Bensi, T., Ferretti, M., Comi, C., Dong, C., Rojo, J.M., Yagi, J., Dianzani, U. Eur. J. Immunol. (2006) [Pubmed]
  13. Eminent role of ICOS costimulation for T cells interacting with plasmacytoid dendritic cells. Janke, M., Witsch, E.J., Mages, H.W., Hutloff, A., Kroczek, R.A. Immunology (2006) [Pubmed]
  14. Expression and function of the co-stimulator H4/ICOS on activated T cells of patients with rheumatoid arthritis. Okamoto, T., Saito, S., Yamanaka, H., Tomatsu, T., Kamatani, N., Ogiuchi, H., Uchiyama, T., Yagi, J. J. Rheumatol. (2003) [Pubmed]
  15. Structural basis of inducible costimulator ligand costimulatory function: determination of the cell surface oligomeric state and functional mapping of the receptor binding site of the protein. Chattopadhyay, K., Bhatia, S., Fiser, A., Almo, S.C., Nathenson, S.G. J. Immunol. (2006) [Pubmed]
  16. AILIM/ICOS-mediated elongation of activated T cells is regulated by both the PI3-kinase/Akt and Rho family cascade. Nukada, Y., Okamoto, N., Konakahara, S., Tezuka, K., Ohashi, K., Mizuno, K., Tsuji, T. Int. Immunol. (2006) [Pubmed]
  17. Upregulated inducible co-stimulator (ICOS) and ICOS-ligand in inclusion body myositis muscle: significance for CD8+ T cell cytotoxicity. Schmidt, J., Rakocevic, G., Raju, R., Dalakas, M.C. Brain (2004) [Pubmed]
  18. Amgen redux: ICOS Corporation. Wells, W.A. Chem. Biol. (1999) [Pubmed]
  19. PI3-kinase and MAP-kinase signaling cascades in AILIM/ICOS- and CD28-costimulated T-cells have distinct functions between cell proliferation and IL-10 production. Okamoto, N., Tezuka, K., Kato, M., Abe, R., Tsuji, T. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  20. ICOS costimulation requires IL-2 and can be prevented by CTLA-4 engagement. Riley, J.L., Blair, P.J., Musser, J.T., Abe, R., Tezuka, K., Tsuji, T., June, C.H. J. Immunol. (2001) [Pubmed]
  21. ICOS-induced B7h shedding on B cells is inhibited by TLR7/8 and TLR9. Logue, E.C., Bakkour, S., Murphy, M.M., Nolla, H., Sha, W.C. J. Immunol. (2006) [Pubmed]
  22. AILIM/ICOS: its expression and functional analysis with monoclonal antibodies. Sakamoto, S., Tezuka, K., Tsuji, T., Hori, N., Tamatani, T. Hybrid. Hybridomics (2001) [Pubmed]
  23. Characterization of human inducible costimulator ligand expression and function. Aicher, A., Hayden-Ledbetter, M., Brady, W.A., Pezzutto, A., Richter, G., Magaletti, D., Buckwalter, S., Ledbetter, J.A., Clark, E.A. J. Immunol. (2000) [Pubmed]
  24. Glomerular infiltration by CXCR3+ ICOS+ activated T cells in chronic allograft nephropathy with transplant glomerulopathy. Akalin, E., Dikman, S., Murphy, B., Bromberg, J.S., Hancock, W.W. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. (2003) [Pubmed]
  25. Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses. Bennett, F., Luxenberg, D., Ling, V., Wang, I.M., Marquette, K., Lowe, D., Khan, N., Veldman, G., Jacobs, K.A., Valge-Archer, V.E., Collins, M., Carreno, B.M. J. Immunol. (2003) [Pubmed]
  26. T-cell costimulatory molecules: optimal targets for the treatment of allergic airway disease with monoclonal antibodies. Kroczek, R., Hamelmann, E. J. Allergy Clin. Immunol. (2005) [Pubmed]
  27. Inducible CO-stimulator molecule, a candidate gene for defective isotype switching, is normal in patients with hyper-IgM syndrome of unknown molecular diagnosis. Lee, W.I., Zhu, Q., Gambineri, E., Jin, Y., Welcher, A.A., Ochs, H.D. J. Allergy Clin. Immunol. (2003) [Pubmed]
  28. Endothelial inducible costimulator ligand expression is increased during human cardiac allograft rejection and regulates endothelial cell-dependent allo-activation of CD8+ T cells in vitro. Klingenberg, R., Autschbach, F., Gleissner, C., Giese, T., Wambsganss, N., Sommer, N., Richter, G., Katus, H.A., Dengler, T.J. Eur. J. Immunol. (2005) [Pubmed]
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