Inducible T-cell costimulator is an
immune checkpoint
Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulat ...
protein that in humans is encoded by the ''ICOS''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
CD278 or ICOS (Inducible T-cell COStimulator) is a CD28-superfamily costimulatory molecule that is expressed on activated
T cells
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell ...
. 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 cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell ...
s activated with plate-bound anti-
CD3 have reduced proliferation and
IL-2
The Ilyushin Il-2 (Russian: Илью́шин Ил-2) is a ground-attack plane that was produced by the Soviet Union in large numbers during the Second World War. The word ''shturmovík'' (Cyrillic: штурмовик), the generic Russian term ...
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
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in a ...
secretion, ICOS-/-
CD4+ T cell activated ''
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and ...
'' 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
An alum () is a type of chemical compound, usually a hydrated double sulfate salt of aluminium with the general formula , where is a monovalent cation such as potassium or ammonium. By itself, "alum" often refers to potassium alum, with t ...
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
Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG a ...
and
IgE antibody titers in response to immunization.
Combination therapy
Ipilimumab
Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.
Cytotoxic T lymphocytes (CTLs) can recogniz ...
patients expressed increased ICOS+ T cells in tumor tissues and blood. The increase served as a pharmacodynamic biomarker of anti-
CTLA-4
CTLA-4 or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 (cluster of differentiation 152), is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA-4 is constitutively exp ...
treatment. In wild-type
C57BL/6
C57BL/6, often referred to as "C57 black 6", "C57" or "black 6", is a common inbred strain of laboratory mouse.
It is the most widely used "genetic background" for genetically modified mice for use as models of human disease. They are the most w ...
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
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ele ...
(
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