Biology:CD278

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Short description: Protein found in humans

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. 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.[8] As of 2015 antibodies for ICOS were not available for clinical testing.[9]

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/gene?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. ↑ "The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo". Journal of Immunology 175 (4): 2340–2348. August 2005. doi:10.4049/jimmunol.175.4.2340. PMID 16081804. 
  7. ↑ "T Cell Inhibitors in Phase 1 and 2 Clinical Studies for Immunological Disorders". Handbook of Therapeutic Antibodies (2nd ed.). Weinheim, Bergstr: Wiley-VCH. 2014. pp. 1088–9. ISBN 978-3-527-32937-3. https://books.google.com/books?id=I9k8BAAAQBAJ&q=ICOS+IL-2+CD3++Th1+Th2&pg=PA1088. 
  8. ↑ "ICOS costimulation in combination with CTLA-4 blockade remodels tumor-associated macrophages toward an antitumor phenotype". The Journal of Experimental Medicine 221 (4). April 2024. doi:10.1084/jem.20231263. PMID 38517331. PMC 10959121. https://doi.org/10.1084/jem.20231263. 
  9. ↑ "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

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



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