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TitleBlocking common γ chain cytokine signaling ameliorates T cell-mediated pathogenesis in disease models.
Journal, issue, pagesSci Transl Med, Vol. 15, Issue 678, Page eabo0205, Year 2023
Publish dateJan 11, 2023
AuthorsAudrey Le Floc'h / Kirsten Nagashima / Dylan Birchard / George Scott / Li-Hong Ben / Dharani Ajithdoss / Kaitlyn Gayvert / Annabel Romero Hernandez / Olivier Herbin / Amanda Tay / Pamela Farrales / Chandrashekhar K Korgaonkar / Hao Pan / Sweta Shah / Vishal Kamat / Ishita Chatterjee / Jon Popke / Adelekan Oyejide / Wei Keat Lim / Jee H Kim / Tammy Huang / Matthew Franklin / William Olson / Thomas Norton / Lorah Perlee / George D Yancopoulos / Andrew J Murphy / Matthew A Sleeman / Jamie M Orengo /
PubMed AbstractThe common γ chain (γc; IL-2RG) is a subunit of the interleukin (IL) receptors for the γc cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The lack of appropriate neutralizing antibodies ...The common γ chain (γc; IL-2RG) is a subunit of the interleukin (IL) receptors for the γc 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 γc cytokines in inflammatory and autoimmune disease settings. Here, we generated a γc cytokine receptor antibody, REGN7257, to determine whether γc 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 γc cytokines. In nonhuman primates, REGN7257 efficiently suppressed T cells without affecting granulocytes, platelets, or red blood cells. Using REGN7257, we showed that γc 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 γc cytokines contribute to GVHD and aplastic anemia pathology by promoting these characteristic features. By demonstrating that broad inhibition of γc cytokine signaling with REGN7257 protects from immune-mediated disorders, our data provide evidence of γc cytokines as key drivers of pathogenic T cell responses, offering a potential strategy for the management of T cell-mediated diseases.
External linksSci Transl Med / PubMed:36630481
MethodsEM (single particle)
Resolution3.4 Å
Structure data

28523

8epa

EMDB-28523, PDB-8epa:
Structure of interleukin receptor common gamma chain (IL2Rgamma) in complex with two antibodies
Method: EM (single particle) / Resolution: 3.4 Å

Source
  • mus musculus (house mouse)
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / interleukin signaling / lymphocyte maturation / blocking antibody / immunoglobulin

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