Description
Human leukocyte antigen (HLA)-G is a non-classical major histocompatibility complex (MHC) class I gene belonging to the HLA class I family. The HLA class I family is subdivided into the classical (HLA-Ia) antigens comprised of HLA-A, -B, and -C molecules and the nonclassical (HLA-Ib) group including the HLA-E, -F, and -G molecules. Seven different splice variants of HLA-G have been observed including four membrane isoforms (HLA-G1, HLA-G2, HLA-G3, and HLA-G4) and three soluble isoforms (HLA-G5, HLA-G6 and HLA-G7). Proteolytic processing of HLA-G1 by metalloproteinases (MMPs) such as MMP-2 produces the soluble isoform, shedding HLA-G1. The HLA-G1 and HLA-G5 isoforms share a similar confirmation to the classical MHC class I protein, consisting of three extracellular domains including alpha1, alpha2, and alpha3 associated with Beta-2-microglobulin (B2M). Other HLA-G variants are shorter, missing one or two of the globular domains and are not bound to B2M. HLA-G receptors include KIR2DL4 (CD158d), with the highest affinity for ILT2 (LILRB1, CD85j) and ILT4 (LILRB2, CD85d) (1,2).
Discovered in cytotrophoblasts, HLA-G is involved in fetal maternal immune tolerance and some studies have linked its downregulation with severe preeclampsia (3). HLA-G mediated immune suppression works by impeding cell proliferation, differentiation, cytotoxicity, cytokine secretion and chemotaxis; and activation of regulatory cells and MDSCs or M2 type macrophage. HLA-G is constitutively expressed in immune-privileged sites such as pancreatic islets, mesenchymal stem cells (MSCs) and the cornea. Upregulation of HLA-G occurs in pathological states including cancer, allo-transplantations, viral infections, autoimmune and inflammatory diseases (4). In cancer, HLA-G expression is induced by hypoxia and has been correlated with advanced tumor stage, tumor metastasis, and poor therapeutic response and survival. HLA-G is an attractive tumor associated-antigen (TAA) for immunotherapy and is considered a major immune checkpoint (ICP).
References
1. Loustau, M., Anna, F., Drean, R., Lecomte, M., Langlade-Demoyen, P., & Caumartin, J. (2020). HLA-G Neo-Expression on Tumors. Front Immunol, 11:1685. PMID: 32922387
2. Lin A, Yan WH. (2018) Heterogeneity of HLA-G Expression in Cancers: Facing the Challenges. Front Immunol. 9:2164. PMID: 30319626
3. Djurisic S, Hviid TV. (2014) HLA Class Ib Molecules and Immune Cells in Pregnancy and Preeclampsia. Front Immunol. 5:652. PMID: 25566263
4. Lila N, Rouas-Freiss N, Dausset J, Carpentier A, Carosella ED. (2001) Soluble HLA-G protein secreted by allo-specific CD4+ T cells suppresses the allo-proliferative response: a CD4+ T cell regulatory mechanism. Proc Natl Acad Sci U S A. 98(21):12150-12155. PMID: 11572934
Bioinformatics
| Entrez |
Human
|
| Uniprot |
Human
Human
|
| Product By Gene ID |
3135 |
| Alternate Names |
- b2 microglobulin
- HLA class I histocompatibility antigen, alpha chain G
- HLA class I molecule
- HLA G antigen
- HLA-6.0
- HLA-G histocompatibility antigen, class I, G
- HLAG
- HLA-G
- major histocompatibility complex, class I, G
- MHC class I antigen G
- MHC class Ib antigen
- MHC-G
- mutant MHC class I antigen
- mutant MHC class Ib antigen
- sHLA-G
- Soluble HLA class I histocompatibility antigen, alpha chain G
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