8epa
From Proteopedia
Structure of interleukin receptor common gamma chain (IL2Rgamma) in complex with two antibodies
Structural highlights
DiseaseIL2RG_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] FunctionIL2RG_HUMAN Common subunit for the receptors for a variety of interleukins. Publication Abstract from PubMedThe 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. Loading citation details.. Citations 1 reviews cite this structure No citations found References
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