ICOS (CD278)

Target id: 2939

Nomenclature: ICOS (CD278)

Family: Other immune checkpoint proteins, CD molecules

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     ICOS (CD278) has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 199 2q33.2 ICOS inducible T cell costimulator 3
Mouse 1 200 1 C2; 1 30.6 cM Icos inducible T cell co-stimulator
Rat 1 200 9q32 Icos inducible T-cell co-stimulator
Previous and Unofficial Names
inducible T-cell costimulator | activation-inducible lymphocyte immunomediatory molecule | AILIM | CVID1 | inducible costimulator
Database Links
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
RefSeq Nucleotide
RefSeq Protein
Natural/Endogenous Ligands
ICOS ligand {Sp: Human}
Immunopharmacology Comments
Inducible T cell costimulator (ICOS) and it's ligand constitute an immune checkpoint. ICOS is a surface receptor on activated T cells that binds its ligand on antigen presenting cells. Ligand-receptor interaction is a T cell activation signal. ICOS is a major regulator of the adaptive immune reponse that is structurally and functionally related to CD28 [3]. One of the major regulators of ICOS expression is Roquin-1 (RC3H1; Q5TC82), an E3 ubiquitin ligase that contributes to the maintenance of immune homeostasis by regulating the expression of a number of immunoregulatory proteins [6]. Roquin-mediated reduction in ICOS mRNA levels results in repression of autoimmunity, and conversley a loss-of-function mutation in mouse Rc3h1 increases T cell Icos expression which leads to an accumulation of lymphocytes and an associated lupus-like autoimmune syndrome [8].

ICOS is being investigated as an immuno-oncology drug target. Agonist-like binding of anti-ICOS monoclonal antibodies (mAbs) to ICOS expressed on tumour infiltrating CD4-positive T cells stimulates ICOS-positive T cell proliferation, enhances cytotoxic T-lymphocyte (CTL) survival and increases CTL-mediated immune responses against tumour cells. Anti-ICOS mAbs such as JTX-2011 and GSK3359609 are being evaluated in early stage clinical trials as either monotherapy or in combination with other immune checkpoint inhibitor mAbs vs. various solid tumour types (JTX-2011: Phase 1/2 NCT02904226 ±anti-PD-1 checkpoint inhihbitor nivolumab; GSK3359609: Phase 1 NCT02723955 ±anti-PD-1 checkpoint inhihbitor pembrolizumab).
Cell Type Associations
Immuno Cell Type:  T cells
Cell Ontology Term:   effector T cell (CL:0000911)
Comment:  ICOS is upregulated on effector and memory T cells during activation. It is also present on peripheral Tregs.
References:  1,4,7
Immuno Process Associations
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes
GO:0038111 interleukin-7-mediated signaling pathway TAS
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 1 GO processes
GO:0031295 T cell costimulation TAS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 1 GO processes
GO:0031295 T cell costimulation TAS
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes
GO:0031295 T cell costimulation TAS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0031295 T cell costimulation TAS
Immuno Process:  Immune system development
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0002517 T cell tolerance induction IEA
Clinically-Relevant Mutations and Pathophysiology
Disease:  Common variable immunodeficiency
Description: CVID is a group of genetically heterogeneous primary immunodeficiencies. Whilst a small number of cases can be linked to deficiency in a single gene (see the OMIM links as examples), the cause is likely to be polygenic in the majority of cases. Symptoms vary between patients, but CVID is generally characterised by a failure to produce antibodies (hypogammaglobulinemia) and therefore susceptibility to recurrent infections and inflammation (including autoimmunity).
Disease Ontology: DOID:12177
OMIM: 613495, 607594, 606453, 240500, 613493
Orphanet: ORPHA1572
References:  2,5
General Comments
ICOS belongs to the CD28 and CTLA-4 cell-surface receptor family. It is active as homodimers and is a costimulatory molecule involved in cell-cell signaling, innate immune responses, and regulation of cell proliferation.


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1. Beier KC, Hutloff A, Dittrich AM, Heuck C, Rauch A, Büchner K, Ludewig B, Ochs HD, Mages HW, Kroczek RA. (2000) Induction, binding specificity and function of human ICOS. Eur. J. Immunol.30 (12): 3707-17. [PMID:11169414]

2. Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Dräger R, Eibel H, Fischer B, Schäffer AA, Mages HW et al.. (2003) Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat. Immunol.4 (3): 261-8. [PMID:12577056]

3. Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I, Kroczek RA. (1999) ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature397 (6716): 263-6. [PMID:9930702]

4. Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA. (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity12 (4): 431-40. [PMID:10795741]

5. Salzer U, Maul-Pavicic A, Cunningham-Rundles C, Urschel S, Belohradsky BH, Litzman J, Holm A, Franco JL, Plebani A, Hammarstrom L et al.. (2004) ICOS deficiency in patients with common variable immunodeficiency. Clin. Immunol.113 (3): 234-40. [PMID:15507387]

6. Schaefer JS, Klein JR. (2016) Roquin--a multifunctional regulator of immune homeostasis. Genes Immun.17 (2): 79-84. [PMID:26673963]

7. Vocanson M, Rozieres A, Hennino A, Poyet G, Gaillard V, Renaudineau S, Achachi A, Benetiere J, Kaiserlian D, Dubois B et al.. (2010) Inducible costimulator (ICOS) is a marker for highly suppressive antigen-specific T cells sharing features of TH17/TH1 and regulatory T cells. J. Allergy Clin. Immunol.126 (2): 280-9, 289.e1-7. [PMID:20624644]

8. Yu D, Tan AH, Hu X, Athanasopoulos V, Simpson N, Silva DG, Hutloff A, Giles KM, Leedman PJ, Lam KP et al.. (2007) Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature450 (7167): 299-303. [PMID:18172933]

How to cite this page

Other immune checkpoint proteins: ICOS (CD278). Last modified on 29/01/2018. Accessed on 20/03/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2939.