| Structural highlights
Disease
IL2RG_HUMAN Defects in IL2RG are the cause of severe combined immunodeficiency X-linked T-cell-negative/B-cell-positive/NK-cell-negative (XSCID) [MIM:300400; also known as agammaglobulinemia Swiss type. A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Defects in IL2RG are the cause of X-linked combined immunodeficiency (XCID) [MIM:312863. XCID is a less severe form of X-linked immunodeficiency with a less severe degree of deficiency in cellular and humoral immunity than that seen in XSCID.[11] [12]
Function
IL2RG_HUMAN Common subunit for the receptors for a variety of interleukins.
Publication Abstract from PubMed
The common gamma chain (gammac; IL-2RG) is a subunit of the interleukin (IL) receptors for the gammac cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The lack of appropriate neutralizing antibodies recognizing IL-2RG has made it difficult to thoroughly interrogate the role of gammac cytokines in inflammatory and autoimmune disease settings. Here, we generated a gammac cytokine receptor antibody, REGN7257, to determine whether gammac cytokines might be targeted for T cell-mediated disease prevention and treatment. Biochemical, structural, and in vitro analysis showed that REGN7257 binds with high affinity to IL-2RG and potently blocks signaling of all gammac cytokines. In nonhuman primates, REGN7257 efficiently suppressed T cells without affecting granulocytes, platelets, or red blood cells. Using REGN7257, we showed that gammac cytokines drive T cell-mediated disease in mouse models of graft-versus-host disease (GVHD) and multiple sclerosis by affecting multiple aspects of the pathogenic response. We found that our xenogeneic GVHD mouse model recapitulates hallmarks of acute and chronic GVHD, with T cell expansion/infiltration into tissues and liver fibrosis, as well as hallmarks of immune aplastic anemia, with bone marrow aplasia and peripheral cytopenia. Our findings indicate that gammac cytokines contribute to GVHD and aplastic anemia pathology by promoting these characteristic features. By demonstrating that broad inhibition of gammac cytokine signaling with REGN7257 protects from immune-mediated disorders, our data provide evidence of gammac cytokines as key drivers of pathogenic T cell responses, offering a potential strategy for the management of T cell-mediated diseases.
Blocking common gamma chain cytokine signaling ameliorates T cell-mediated pathogenesis in disease models.,Le Floc'h A, Nagashima K, Birchard D, Scott G, Ben LH, Ajithdoss D, Gayvert K, Romero Hernandez A, Herbin O, Tay A, Farrales P, Korgaonkar CK, Pan H, Shah S, Kamat V, Chatterjee I, Popke J, Oyejide A, Lim WK, Kim JH, Huang T, Franklin M, Olson W, Norton T, Perlee L, Yancopoulos GD, Murphy AJ, Sleeman MA, Orengo JM Sci Transl Med. 2023 Jan 11;15(678):eabo0205. doi: 10.1126/scitranslmed.abo0205. , Epub 2023 Jan 11. PMID:36630481[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Puck JM, Deschenes SM, Porter JC, Dutra AS, Brown CJ, Willard HF, Henthorn PS. The interleukin-2 receptor gamma chain maps to Xq13.1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1. Hum Mol Genet. 1993 Aug;2(8):1099-104. PMID:8401490
- ↑ DiSanto JP, Dautry-Varsat A, Certain S, Fischer A, de Saint Basile G. Interleukin-2 (IL-2) receptor gamma chain mutations in X-linked severe combined immunodeficiency disease result in the loss of high-affinity IL-2 receptor binding. Eur J Immunol. 1994 Feb;24(2):475-9. PMID:8299698
- ↑ Markiewicz S, Subtil A, Dautry-Varsat A, Fischer A, de Saint Basile G. Detection of three nonsense mutations and one missense mutation in the interleukin-2 receptor gamma chain gene in SCIDX1 that differently affect the mRNA processing. Genomics. 1994 May 1;21(1):291-3. PMID:8088810 doi:http://dx.doi.org/10.1006/geno.1994.1265
- ↑ Ishii N, Asao H, Kimura Y, Takeshita T, Nakamura M, Tsuchiya S, Konno T, Maeda M, Uchiyama T, Sugamura K. Impairment of ligand binding and growth signaling of mutant IL-2 receptor gamma-chains in patients with X-linked severe combined immunodeficiency. J Immunol. 1994 Aug 1;153(3):1310-7. PMID:8027558
- ↑ DiSanto JP, Rieux-Laucat F, Dautry-Varsat A, Fischer A, de Saint Basile G. Defective human interleukin 2 receptor gamma chain in an atypical X chromosome-linked severe combined immunodeficiency with peripheral T cells. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9466-70. PMID:7937790
- ↑ Pepper AE, Buckley RH, Small TN, Puck JM. Two mutational hotspots in the interleukin-2 receptor gamma chain gene causing human X-linked severe combined immunodeficiency. Am J Hum Genet. 1995 Sep;57(3):564-71. PMID:7668284
- ↑ Clark PA, Lester T, Genet S, Jones AM, Hendriks R, Levinsky RJ, Kinnon C. Screening for mutations causing X-linked severe combined immunodeficiency in the IL-2R gamma chain gene by single-strand conformation polymorphism analysis. Hum Genet. 1995 Oct;96(4):427-32. PMID:7557965
- ↑ Puck JM, Pepper AE, Bedard PM, Laframboise R. Female germ line mosaicism as the origin of a unique IL-2 receptor gamma-chain mutation causing X-linked severe combined immunodeficiency. J Clin Invest. 1995 Feb;95(2):895-9. PMID:7860773 doi:http://dx.doi.org/10.1172/JCI117740
- ↑ Stephan V, Wahn V, Le Deist F, Dirksen U, Broker B, Muller-Fleckenstein I, Horneff G, Schroten H, Fischer A, de Saint Basile G. Atypical X-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells. N Engl J Med. 1996 Nov 21;335(21):1563-7. PMID:8900089 doi:10.1056/NEJM199611213352104
- ↑ Jones AM, Clark PA, Katz F, Genet S, McMahon C, Alterman L, Cant A, Kinnon C. B-cell-negative severe combined immunodeficiency associated with a common gamma chain mutation. Hum Genet. 1997 May;99(5):677-80. PMID:9150740
- ↑ Schmalstieg FC, Leonard WJ, Noguchi M, Berg M, Rudloff HE, Denney RM, Dave SK, Brooks EG, Goldman AS. Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency. J Clin Invest. 1995 Mar;95(3):1169-73. PMID:7883965 doi:http://dx.doi.org/10.1172/JCI117765
- ↑ Sharfe N, Shahar M, Roifman CM. An interleukin-2 receptor gamma chain mutation with normal thymus morphology. J Clin Invest. 1997 Dec 15;100(12):3036-43. PMID:9399950 doi:10.1172/JCI119858
- ↑ Le Floc'h A, Nagashima K, Birchard D, Scott G, Ben LH, Ajithdoss D, Gayvert K, Romero Hernandez A, Herbin O, Tay A, Farrales P, Korgaonkar CK, Pan H, Shah S, Kamat V, Chatterjee I, Popke J, Oyejide A, Lim WK, Kim JH, Huang T, Franklin M, Olson W, Norton T, Perlee L, Yancopoulos GD, Murphy AJ, Sleeman MA, Orengo JM. Blocking common gamma chain cytokine signaling ameliorates T cell-mediated pathogenesis in disease models. Sci Transl Med. 2023 Jan 11;15(678):eabo0205. doi: 10.1126/scitranslmed.abo0205. , Epub 2023 Jan 11. PMID:36630481 doi:http://dx.doi.org/10.1126/scitranslmed.abo0205
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