CD278

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Inducible T-cell co-stimulator
Identifiers
Symbols ICOS ; AILIM; CD278; CVID1
External IDs OMIM604558 MGI1858745 HomoloGene8097 GeneCards: ICOS Gene
RNA expression pattern
PBB GE ICOS 210439 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 29851 54167
Ensembl ENSG00000163600 ENSMUSG00000026009
UniProt Q9Y6W8 Q9WVS0
RefSeq (mRNA) NM_012092 NM_017480
RefSeq (protein) NP_036224 NP_059508
Location (UCSC) Chr 2:
203.94 – 203.96 Mb
Chr 1:
60.98 – 61 Mb
PubMed search [1] [2]

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]

Function[edit]

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]

ICOS knockout phenotype[edit]

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 have reduced IL-4 secretion, but 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 have reduced germinal center formation and IgG1 and IgE antibody titers in response to immunization.

Combination therapy[edit]

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, 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]

References[edit]

  1. ^ Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I et al. (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 et al. (Dec 1999). "T-cell co-stimulation through B7RP-1 and ICOS". Nature 402 (6763): 827–32. doi:10.1038/45582. PMID 10617205. 
  3. ^ a b "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 et al. (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[edit]

External links[edit]

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