ICOSLG is glycosylated transmembrane structure, which is classified as a member of theB7 family due to the significant homology with B7 family members. The B7/CD28 superfamily provides both positive and negative co-signals toimmunocytes inimmune responses.
The interaction of ICOSLG withICOS, the specificreceptor for ICOSLG, is critically involved in the activation, proliferation, differentiation andcytokine production ofT cells as well as in theantibody secretion fromB cells during secondary immune responses.[8]
ICOSLG, which is extensively expressed in both non-lymphatic andlymphatic tissues, is an important molecule in upregulating and promoting T cell immune responses. Expression of ICOSLG innaive B cells and monocytes inPBMCs is at a low level. After stimulation byIFN-γ,TNF-α, orLPS, it can be quickly up-regulated. The induced expression of ICOS on activated T cells mainly regulates the secretion ofTh2 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 asinfection,hypersensitivity,autoimmune diseases, transplantation immunity and tumor immunity.
ICOSLG is also a majorcostimulator inendothelial 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.[9]
Inducible costimulator-ligand (ICOS-L) is a member of the B7 family of costimulatory ligands[10] sharing 19–20% sequence identity with CD80 and CD86. Twosplice variants of human ICOSLG have been described and designated hICOSLG and B7-H2/B7RP-1/hLICOS.[11]
Both molecules have an identicalextracellular domain but differ at thecarboxyl-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).[12]
Murine ICOSLG, unlikeCD80 andCD86, does not interact withCD28 orCTLA-4 (CD152). Instead, ICOSLG binds to ICOS, a T cell-specific costimulatory molecule homologous to CD28 andCTLA-4.[13] In humans, ICOSLG binds to ICOS but also to CD28 and CTLA-4.[14]
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 inisotype class switching in T cell-dependent B cell responses, and are defective inIL-4 andIL-13 production. In addition, blockade of ICOS/ICOSLG interaction in animal models ofexperimental allergic encephalomyelitis and of cardiac allograft rejection revealed a critical role of ICOS and its ligand in inflammatory immune reactions.[9]
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 andneutrophils across endothelial cells, which normally express ICOSLG. These defects contributed with altered adaptive immunity andneutropenia in patient, thus showing ICOSLG deficiency as a cause ofcombined immunodeficiency.[15]
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.[8]
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 inTregs. Therefore, both agonistic and antagonisticmonoclonal antibodies (mAbs) targeting this pathway are being investigated for cancer immunotherapy.[16] 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.[17]
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.[18]
^abShen S, Wang F, Chen L, Wang T, Hu Y, Zhang X (August 2011). "Immunoreactivity of two novel monoclonal antibodies against human inducible co-stimulator ligand".Hybridoma.30 (4):361–368.doi:10.1089/hyb.2011.0014.PMID21851236.
^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.PMID11224518.S2CID20542148.
^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.PMID11023515.
^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.PMID29468927.S2CID4774208.
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.PMID11023515.
Sperling AI, Bluestone JA (July 2001). "ICOS costimulation: It's not just for TH2 cells anymore".Nature Immunology.2 (7):573–574.doi:10.1038/89709.PMID11429535.S2CID31317654.
Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH, et al. (September 2002). "Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity".Nature Medicine.8 (9):1024–1032.doi:10.1038/nm745.PMID12145647.S2CID30454021.
Kurosawa S, Myers AC, Chen L, Wang S, Ni J, Plitt JR, et al. (May 2003). "Expression of the costimulatory molecule B7-H2 (inducible costimulator ligand) by human airway epithelial cells".American Journal of Respiratory Cell and Molecular Biology.28 (5):563–573.doi:10.1165/rcmb.2002-0199OC.PMID12707012.
Schreiner B, Wischhusen J, Mitsdoerffer M, Schneider D, Bornemann A, Melms A, et al. (December 2003). "Expression of the B7-related molecule ICOSL by human glioma cells in vitro and in vivo".Glia.44 (3):296–301.doi:10.1002/glia.10291.PMID14603470.S2CID25318238.
Saatian B, Yu XY, Yu X, Lane AP, Doyle T, Casolaro V, Spannhake EW (July 2004). "Expression of genes for B7-H3 and other T cell ligands by nasal epithelial cells during differentiation and activation".American Journal of Physiology. Lung Cellular and Molecular Physiology.287 (1):L217 –L225.doi:10.1152/ajplung.00132.2003.PMID15047568.
