# ICOSLG

ICOS ligand is a protein that in humans is encoded by the ICOSLG gene located at chromosome 21. ICOSLG has also been designated as CD275 (cluster of differentiation 275).
ICOSLG is glycosylated transmembrane structure, which is classified as a member of the B7 family due to the significant homology with B7 family members. The B7/CD28 superfamily provides both positive and negative co-signals to immunocytes in immune responses.
The interaction of ICOSLG with ICOS, the specific receptor for ICOSLG, is critically involved in the activation, proliferation, differentiation and cytokine production of T cells as well as in the antibody secretion from B cells during secondary immune responses.
ICOSLG, which is extensively expressed in both non-lymphatic and lymphatic tissues, is an important molecule in upregulating and promoting T cell immune responses. Expression of ICOSLG in naive B cells and monocytes in PBMCs is at a low level. After stimulation by IFN-γ, TNF-α, or LPS, it can be quickly up-regulated. The induced expression of ICOS on activated T cells mainly regulates the secretion of Th2 cytokines and thus shifts the immune response to the Th2 type. It has been reported that the ICOS/ICOSLG pathway is involved in immunopathogenesis such as infection, hypersensitivity, autoimmune diseases, transplantation immunity and tumor immunity.
ICOSLG is also a major costimulator in endothelial cell-mediated T cell activation. It has an important physiological role of ICOSLG in the reactivation of effector/memory T cells on the endothelium controlling the entry of immune cells into inflamed tissue.

## Structure

Inducible costimulator-ligand (ICOS-L) is a member of the B7 family of costimulatory ligands sharing 19–20% sequence identity with CD80 and CD86. Two splice variants of human ICOSLG have been described and designated hICOSLG and B7-H2/B7RP-1/hLICOS.
Both molecules have an identical extracellular domain but differ at the carboxyl-terminal end of their cytoplasmic regions. In humans, cell surface expression of ICOSLG has been described on B cells, dendritic cells, monocytes/macrophages, and T cells. In addition, mRNA expression of ICOSLG has been detected in a variety of lymphoid and nonlymphoid organs, with hICOSLG showing a more lymphoid-restricted expression pattern (spleen, lymph node), whereas B7-H2/B7RP-1/hLICOSmRNA was expressed in all organs examined (e.g., spleen, kidney, heart, and brain).

## Interaction

Murine ICOSLG, unlike CD80 and CD86, does not interact with CD28 or CTLA-4 (CD152). Instead, ICOSLG binds to ICOS, a T cell-specific costimulatory molecule homologous to CD28 and CTLA-4. In humans, ICOSLG binds to ICOS but also to CD28 and CTLA-4.
The strong impact of ICOS/ICOSLG interaction on T cell-mediated immune responses in vivo became evident by the disruption of the ICOS gene in mice. ICOS deficient mice are characterized by impaired germinal center formation, have a profound defect in isotype class switching in T cell-dependent B cell responses, and are defective in IL-4 and IL-13 production. In addition, blockade of ICOS/ICOSLG interaction in animal models of experimental allergic encephalomyelitis and of cardiac allograft rejection revealed a critical role of ICOS and its ligand in inflammatory immune reactions.

## Immunodeficiencies

The research with mutant ICOSLG showed that if the protein was retained in ER/GA, instead of the cell surface in normal case, it diminished B cell costimulation of T cells. It led to defect in antibody and memory B cell generation. Mutant ICOSLG also impaired migration of lymphocytes and neutrophils across endothelial cells, which normally express ICOSLG. These defects contributed with altered adaptive immunity and neutropenia in patient, thus showing ICOSLG deficiency as a cause of combined immunodeficiency.

## Immunotherapy

The fluctuant balance between co-stimulatory and coinhibitory signals that a T cell receives participates in the initiation, effection, and termination of an immune response. Excessive activation and immune reaction of T cells may result in autoimmune diseases and host immune injury.
ICOSLG delivers a potent co-stimulatory signal to T cells when engaged by ICOS, resulting in T cell activation and proliferation. The existence of ICOS/ICOSLG signal in vivo is closely associated with many mouse autoimmune disease models. Conversely, the absence of ICOS/ICOSLG signal may be a good way to relieve autoimmune disease. In view of its critical function in regulating immunohomeostasis, ICOS signaling has aroused great attention in immunodiagnosis and therapy.
The ICOS/ICOSLG axis has been shown to promote either antitumor T cell responses (when activated in Th1 and other Teff) or protumor responses when triggered in Tregs. Therefore, both agonistic and antagonistic monoclonal antibodies (mAbs) targeting this pathway are being investigated for cancer immunotherapy. Stimulation of the ICOS pathway by tumor cell vaccine expressing ICOSLG, in combination with anti-CTLA-4 therapy blockade, led to enhanced antitumor efficacy. This combined treatment approach, which integrates ICOS costimulation through ICOSLG and CTLA-4 blockade, effectively alters tumor-associated macrophages (TAMs) towards a phenotype that fights against tumors, showing significant promise for cancer treatment.
Undoubtedly, the development of more efficient and specific monoclonal antibodies may be important for further disclosure of ICOSLG function. Agonistic Abs are currently being administered either alone or in combination with immunotherapy and chemotherapy.

## References list

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* 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000000732 – Ensembl, May 2017
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* ↑ Yoshinaga SK, Zhang M, Pistillo J, Horan T, Khare SD, Miner K, et al. (October 2000). "Characterization of a new human B7-related protein: B7RP-1 is the ligand to the co-stimulatory protein ICOS". International Immunology. 12 (10): 1439–1447. doi:10.1093/intimm/12.10.1439. PMID 11007762.
* ↑ "Entrez Gene: ICOSLG inducible T-cell co-stimulator ligand".
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* 1 2 Khayyamian S, Hutloff A, Büchner K, Gräfe M, Henn V, Kroczek RA, Mages HW (April 2002). "ICOS-ligand, expressed on human endothelial cells, costimulates Th1 and Th2 cytokine secretion by memory CD4+ T cells". Proceedings of the National Academy of Sciences of the United States of America. 99 (9): 6198–6203. Bibcode:2002PNAS...99.6198K. doi:10.1073/pnas.092576699. PMC 122926. PMID 11983910.
* ↑ Coyle AJ, Gutierrez-Ramos JC (March 2001). "The expanding B7 superfamily: increasing complexity in costimulatory signals regulating T cell function". Nature Immunology. 2 (3): 203–209. doi:10.1038/85251. PMID 11224518. S2CID 20542148.
* ↑ Wang S, Zhu G, Chapoval AI, Dong H, Tamada K, Ni J, Chen L (October 2000). "Costimulation of T cells by B7-H2, a B7-like molecule that binds ICOS". Blood. 96 (8): 2808–2813. doi:10.1182/blood.V96.8.2808. PMID 11023515.
* ↑ Ling V, Wu PW, Miyashiro JS, Marusic S, Finnerty HF, Collins M (June 2001). "Differential expression of inducible costimulator-ligand splice variants: lymphoid regulation of mouse GL50-B and human GL50 molecules". Journal of Immunology. 166 (12): 7300–7308. doi:10.4049/jimmunol.166.12.7300. PMID 11390480.
* ↑ Yoshinaga SK, Whoriskey JS, Khare SD, Sarmiento U, Guo J, Horan T, et al. (December 1999). "T-cell co-stimulation through B7RP-1 and ICOS". Nature. 402 (6763): 827–832. Bibcode:1999Natur.402..827Y. doi:10.1038/45582. PMID 10617205. S2CID 4360410.
* ↑ Yao S, Zhu Y, Zhu G, Augustine M, Zheng L, Goode DJ, et al. (May 2011). "B7-h2 is a costimulatory ligand for CD28 in human". Immunity. 34 (5): 729–740. doi:10.1016/j.immuni.2011.03.014. PMC 3103603. PMID 21530327.
* ↑ Roussel L, Landekic M, Golizeh M, Gavino C, Zhong MC, Chen J, et al. (December 2018). "Loss of human ICOSL results in combined immunodeficiency". The Journal of Experimental Medicine. 215 (12): 3151–3164. doi:10.1084/jem.20180668. PMC 6279397. PMID 30498080.
* ↑ Amatore F, Gorvel L, Olive D (April 2018). "Inducible Co-Stimulator (ICOS) as a potential therapeutic target for anti-cancer therapy". Expert Opinion on Therapeutic Targets. 22 (4): 343–351. doi:10.1080/14728222.2018.1444753. PMID 29468927. S2CID 4774208.
* ↑ Sharma N, Fan X, Atolagbe OT, Ge Z, Dao KN, Sharma P, Allison JP (April 2024). "ICOS costimulation in combination with CTLA-4 blockade remodels tumor-associated macrophages toward an antitumor phenotype". The Journal of Experimental Medicine. 221 (4). doi:10.1084/jem.20231263. PMC 10959121. PMID 38517331.
* ↑ Solinas C, Gu-Trantien C, Willard-Gallo K (January 2020). "The rationale behind targeting the ICOS-ICOS ligand costimulatory pathway in cancer immunotherapy". ESMO Open. 5 (1): e000544. doi:10.1136/esmoopen-2019-000544. PMC 7003380. PMID 32516116.