Inducible T-cell costimulator is an
immune checkpoint protein that in humans is encoded by the ''ICOS''
gene.
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.
Function
The protein encoded by this gene belongs to the CD28 and CTLA-4 cell-surface receptor family. It forms
homodimers
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
and plays an important role in cell-cell signaling, immune responses and regulation of cell proliferation.
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.
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
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
cytokine secretion, ICOS-/-
CD4+ T cell activated ''
in vitro'' reduced
IL-4 secretion, while maintaining similar
IFN-g
Interferon gamma (IFN-γ) is a protein dimer, dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by ...
secretion. Similarly, CD4+ T cells purified from ICOS-/- mice immunized with the protein
keyhole limpet hemocyanin (KLH) in
alum
An alum () is a type of chemical compound, usually a hydrated double salt, double sulfate salt (chemistry), salt of aluminium with the general chemical formula, formula , where is a valence (chemistry), monovalent cation such as potassium or a ...
or complete
Freund's Adjuvant have attenuated IL-4 secretion, but similar IFN-g and
IL-5 IL 5 or IL-5 may refer to:
* Interleukin 5
* Illinois's 5th congressional district
* Illinois Route 5
Illinois Route 5 (IL 5) is a four-lane road in Rock Island County, Illinois, United States, that runs from U.S. Route 67 (US 67) in ...
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.
References
Further reading
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External links
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{{CD28 family receptors
Clusters of differentiation