Inducible T-cell costimulator (also called CD278) is an immune checkpoint protein that in humans is encoded by the ICOS (Inducible T-cell COStimulator) gene.[5][6][7][8][9]
The protein belongs to the CD28 and CTLA-4 cell-surface receptor family. These are proteins expressed on the surface of immune cells that mediate signalling between them. A surface protein, the ligand, binds specifically to its receptor on another cell, leading to a signalling cascade in that cell.
ICOS is a receptor protein expressed on the surface of activated T cells. Its ligand ICOS-L (previously called B7RP-1) is constitutively expressed on B cells. Stimulation of the ICOS receptor on T cells by ICOS-L on B cells is required for the development of follicular helper T (Tfh) cells.
[10]
ICOS forms homodimers and plays an important role in cell-cell signaling, immune responses and regulation of cell proliferation.[7]
Compared to wild-type naïve T cells, ICOS-/- T cells activated with plate-bound anti-CD3 have reduced proliferation and IL-2 secretion.[11] 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 Th2cytokine 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.
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. This combination therapy incorporating ICOS costimulation and CTLA-4 blockade effectively remodels tumor-associated macrophages (TAMs) towards an antitumor phenotype, demonstrating promising therapeutic potential in cancer treatment.[12] As of 2015 antibodies for ICOS were not available for clinical testing.[13]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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. Bibcode:1999Natur.397..263H. doi:10.1038/16717. PMID9930702. S2CID4415254.
^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. Bibcode:1999Natur.402..827Y. doi:10.1038/45582. PMID10617205. S2CID4360410.
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. PMID10964520.
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. PMID11006126.
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. doi:10.1182/blood.V96.8.2808. PMID11023515.
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. PMID11735222.
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. PMID11771526. S2CID21094500.
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. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC139241. PMID12477932.
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. PMID12577056. S2CID20069932.
