Biology:CD278

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1][2][3] [4][5] 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.

Function

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. [6] ICOS 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.[7] 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.[8]

References

  1. ↑ "ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28". Nature 397 (6716): 263–6. Jan 1999. doi:10.1038/16717. PMID 9930702. Bibcode: 1999Natur.397..263H. 
  2. ↑ "T-cell co-stimulation through B7RP-1 and ICOS". Nature 402 (6763): 827–32. Dec 1999. doi:10.1038/45582. PMID 10617205. Bibcode: 1999Natur.402..827Y. 
  3. ↑ 3.0 3.1 "Entrez Gene: ICOS inducible T-cell co-stimulator". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=29851. 
  4. ↑ "Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling". Nature Reviews. Immunology 3 (7): 544–56. Jul 2003. doi:10.1038/nri1131. PMID 12876557. 
  5. ↑ "ICOS co-stimulatory receptor is essential for T-cell activation and function". Nature 409 (6816): 97–101. Jan 2001. doi:10.1038/35051100. PMID 11343121. Bibcode: 2001Natur.409...97D. 
  6. ↑ Akiba, Hisaya. "The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo". The Journal of Immunology 175 (4): 2340-2348. doi:10.4049/jimmunol.175.4.2340. https://doi.org/10.4049/jimmunol.175.4.2340. 
  7. ↑ Brennan, Frank R. (2014). "T Cell Inhibitors in Phase 1 and 2 Clinical Studies for Immunological Disorders". Handbook of Therapeutic Antibodies (2 ed.). Weinheim, Bergstr: Wiley-VCH. pp. 1088–9. ISBN 978-3527329373. https://books.google.com/books?id=I9k8BAAAQBAJ&q=ICOS+IL-2+CD3++Th1+Th2&pg=PA1088. 
  8. ↑ "The future of immune checkpoint therapy". Science 348 (6230): 56–61. Apr 2015. doi:10.1126/science.aaa8172. PMID 25838373. Bibcode: 2015Sci...348...56S. 

Further reading

External links

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



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