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Inducible T-cell costimulator is an immune checkpoint protein that in humans is encoded by the ICOS gene.[1][2][3]

CD278 or ICOS (Inducible T-cell COStimulator) is a CD28-superfamily costimulatory molecule that is expressed on activated T cells. It is thought to be important for Th2 cells in particular.[4][5]


The protein encoded by this gene belongs to the CD28 and CTLA-4 cell-surface receptor family. It forms homodimers and plays an important role in cell-cell signaling, immune responses and regulation of cell proliferation.[3]

Knockout phenotype

Compared to wild-type naïve T cells, ICOS-/- T cells activated with plate-bound anti-CD3 have reduced proliferation and IL-2 secretion.[6] The defect in proliferation can be rescued by addition of IL-2 to the culture, suggesting the proliferative defect is due either to ICOS-mediated IL-2 secretion or the activation of similar signaling pathways between ICOS and IL-2. In terms of Th1 and Th2 cytokine secretion, ICOS-/- CD4+ T cell activated in vitro reduced IL-4 secretion, while maintaining similar IFN-g secretion. Similarly, CD4+ T cells purified from ICOS-/- mice immunized with the protein keyhole limpet hemocyanin (KLH) in alum or complete Freund's Adjuvant have attenuated IL-4 secretion, but similar IFN-g and IL-5 secretion when recalled with KLH.

These data are similar to an airway hypersensitivity model showing similar IL-5 secretion, but reduced IL-4 secretion in response to sensitization with Ova protein, indicating a defect in Th2 cytokine secretion, but not a defect in Th1 differentiation as both IL-4 and IL-5 are Th2-associated cytokines. In agreement with reduced Th2 responses, ICOS-/- mice expressed reduced germinal center formation and IgG1 and IgE antibody titers in response to immunization.

Combination therapy

Ipilimumab patients expressed increased ICOS+ T cells in tumor tissues and blood. The increase served as a pharmacodynamic biomarker of anti-CTLA-4 treatment. In wild-type C57BL/6 mice, anti-CTLA-4 treatment resulted in tumor rejection in 80 to 90% of subjects, but in gene-targeted mice that were deficient for either ICOS or its ligand (ICOSLG), the efficacy was less than 50%. An agonistic stimulus for the ICOS pathway during anti-CTLA-4 therapy resulted in an increase in efficacy that was about four to five times as large as that of control treatments. As of 2015 antibodies for ICOS were not available for clinical testing.[7]


  1. Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I, Kroczek RA (Jan 1999). "ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28". Nature. 397 (6716): 263–6. doi:10.1038/16717. PMID 9930702.
  2. Yoshinaga SK, Whoriskey JS, Khare SD, Sarmiento U, Guo J, Horan T, Shih G, Zhang M, Coccia MA, Kohno T, Tafuri-Bladt A, Brankow D, Campbell P, Chang D, Chiu L, Dai T, Duncan G, Elliott GS, Hui A, McCabe SM, Scully S, Shahinian A, Shaklee CL, Van G, Mak TW, Senaldi G (Dec 1999). "T-cell co-stimulation through B7RP-1 and ICOS". Nature. 402 (6763): 827–32. doi:10.1038/45582. PMID 10617205.
  3. 3.0 3.1 "Entrez Gene: ICOS inducible T-cell co-stimulator".
  4. Rudd CE, Schneider H (Jul 2003). "Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling". Nature Reviews. Immunology. 3 (7): 544–56. doi:10.1038/nri1131. PMID 12876557.
  5. Dong C, Juedes AE, Temann UA, Shresta S, Allison JP, Ruddle NH, Flavell RA (Jan 2001). "ICOS co-stimulatory receptor is essential for T-cell activation and function". Nature. 409 (6816): 97–101. doi:10.1038/35051100. PMID 11343121.
  6. Brennan FR (2014). "T Cell Inhibitors in Phase 1 and 2 Clinical Studies for Immunological Disorders". In Dübel S, Reichert JM. Handbook of Therapeutic Antibodies (2 ed.). Weinheim, Bergstr: Wiley-VCH. pp. 1088–9. ISBN 978-3527329373.
  7. Sharma P, Allison JP (Apr 2015). "The future of immune checkpoint therapy". Science. 348 (6230): 56–61. doi:10.1126/science.aaa8172. PMID 25838373.

Further reading

  • Flesch IE (2003). "Inducible costimulator (ICOS)". Journal of Biological Regulators and Homeostatic Agents. 16 (3): 214–6. PMID 12456021.
  • Shilling RA, Bandukwala HS, Sperling AI (Oct 2006). "Regulation of T:B cell interactions by the inducible costimulator molecule: does ICOS "induce" disease?". Clinical Immunology. 121 (1): 13–8. doi:10.1016/j.clim.2006.04.574. PMID 16790364.
  • Ling V, Wu PW, Finnerty HF, Bean KM, Spaulding V, Fouser LA, Leonard JP, Hunter SE, Zollner R, Thomas JL, Miyashiro JS, Jacobs KA, Collins M (Feb 2000). "Cutting edge: identification of GL50, a novel B7-like protein that functionally binds to ICOS receptor". Journal of Immunology. 164 (4): 1653–7. doi:10.4049/jimmunol.164.4.1653. PMID 10657606.
  • Aicher A, Hayden-Ledbetter M, Brady WA, Pezzutto A, Richter G, Magaletti D, Buckwalter S, Ledbetter JA, Clark EA (May 2000). "Characterization of human inducible costimulator ligand expression and function". Journal of Immunology. 164 (9): 4689–96. doi:10.4049/jimmunol.164.9.4689. PMID 10779774.
  • Machado RD, Pauciulo MW, Fretwell N, Veal C, Thomson JR, Vilariño Güell C, Aldred M, Brannon CA, Trembath RC, Nichols WC (Sep 2000). "A physical and transcript map based upon refinement of the critical interval for PPH1, a gene for familial primary pulmonary hypertension. The International PPH Consortium". Genomics. 68 (2): 220–8. doi:10.1006/geno.2000.6291. PMID 10964520.
  • Tezuka K, Tsuji T, Hirano D, Tamatani T, Sakamaki K, Kobayashi Y, Kamada M (Sep 2000). "Identification and characterization of rat AILIM/ICOS, a novel T-cell costimulatory molecule, related to the CD28/CTLA4 family". Biochemical and Biophysical Research Communications. 276 (1): 335–45. doi:10.1006/bbrc.2000.3466. PMID 11006126.
  • Wang S, Zhu G, Chapoval AI, Dong H, Tamada K, Ni J, Chen L (Oct 2000). "Costimulation of T cells by B7-H2, a B7-like molecule that binds ICOS". Blood. 96 (8): 2808–13. PMID 11023515.
  • Breitfeld D, Ohl L, Kremmer E, Ellwart J, Sallusto F, Lipp M, Förster R (Dec 2000). "Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production". The Journal of Experimental Medicine. 192 (11): 1545–52. doi:10.1084/jem.192.11.1545. PMC 2193094. PMID 11104797.
  • Beier KC, Hutloff A, Dittrich AM, Heuck C, Rauch A, Büchner K, Ludewig B, Ochs HD, Mages HW, Kroczek RA (Dec 2000). "Induction, binding specificity and function of human ICOS". European Journal of Immunology. 30 (12): 3707–17. doi:10.1002/1521-4141(200012)30:12<3707::AID-IMMU3707>3.0.CO;2-Q. PMID 11169414.
  • Ling V, Wu PW, Finnerty HF, Agostino MJ, Graham JR, Chen S, Jussiff JM, Fisk GJ, Miller CP, Collins M (Dec 2001). "Assembly and annotation of human chromosome 2q33 sequence containing the CD28, CTLA4, and ICOS gene cluster: analysis by computational, comparative, and microarray approaches". Genomics. 78 (3): 155–68. doi:10.1006/geno.2001.6655. PMID 11735222.
  • Lee YH, Ji JD, Sohn J, Song GG (2002). "Polymorphsims of CTLA-4 exon 1 +49, CTLA-4 promoter -318 and Fas promoter -670 in spondyloarthropathies". Clinical Rheumatology. 20 (6): 420–2. doi:10.1007/s100670170007. PMID 11771526.
  • Haimila KE, Partanen JA, Holopainen PM (Mar 2002). "Genetic polymorphism of the human ICOS gene". Immunogenetics. 53 (12): 1028–32. doi:10.1007/s00251-002-0431-2. PMID 11904679.
  • Wang S, Zhu G, Tamada K, Chen L, Bajorath J (Apr 2002). "Ligand binding sites of inducible costimulator and high avidity mutants with improved function". The Journal of Experimental Medicine. 195 (8): 1033–41. doi:10.1084/jem.20011607. PMC 2193694. PMID 11956294.
  • Riley JL, Mao M, Kobayashi S, Biery M, Burchard J, Cavet G, Gregson BP, June CH, Linsley PS (Sep 2002). "Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors". Proceedings of the National Academy of Sciences of the United States of America. 99 (18): 11790–5. doi:10.1073/pnas.162359999. PMC 129347. PMID 12195015.
  • Witsch EJ, Peiser M, Hutloff A, Büchner K, Dorner BG, Jonuleit H, Mages HW, Kroczek RA (Sep 2002). "ICOS and CD28 reversely regulate IL-10 on re-activation of human effector T cells with mature dendritic cells". European Journal of Immunology. 32 (9): 2680–6. doi:10.1002/1521-4141(200209)32:9<2680::AID-IMMU2680>3.0.CO;2-6. PMID 12207353.
  • Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA (Dec 2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proceedings of the National Academy of Sciences of the United States of America. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
  • Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Dräger R, Eibel H, Fischer B, Schäffer AA, Mages HW, Kroczek RA, Peter HH (Mar 2003). "Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency". Nature Immunology. 4 (3): 261–8. doi:10.1038/ni902. PMID 12577056.

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.