title: CTL-Promoting Effects of IL-21 Counteract Murine Lupus in the Parent→F1 Graft-versus-Host Disease Model.
abstract: IL-21 promotes B cell and CTL responses in vivo, conferring IL-21 with a role in both humoral and cellular responses. Because CTL can target and eliminate autoreactive B cells, we investigated whether IL-21R signaling in CD8 T cells would alter the expansion of autoreactive B cells in an autoimmune setting. We addressed this question using the parent→F1 murine model of acute and chronic (lupus-like) graft-versus-host disease (GVHD) as models of a CTL-mediated or T-dependent B cell-mediated response, respectively. Induction of acute GVHD using IL-21R-deficient donor T cells resulted in decreased peak donor CD8 T cell numbers and decreased CTL effector function due to impaired granzyme B/perforin and Fas/Fas ligand pathways and a phenotype of low-intensity chronic GVHD with persistent host B cells, autoantibody production, and mild lupus-like renal disease. CTL effector maturation was critically dependent on IL-21R signaling in Ag-specific donor CD8, but not CD4, T cells. Conversely, treatment of DBA/2J→F1 chronic GVHD mice with IL-21 strongly promoted donor CD8 T cell expansion and rescued defective donor anti-host CTLs, resulting in host B cell elimination, decreased autoantibody levels, and attenuated renal disease, despite evidence of concurrently enhanced CD4 help for B cells and heightened B cell activation. These results demonstrate that, in the setting of lupus-like CD4 T cell-driven B cell hyperactivity, IL-21 signaling on Ag-specific donor CD8 T cells is critical for CTL effector maturation, whereas a lack of IL-21R downregulates CTL responses that would otherwise limit B cell hyperactivity and autoantibody production.
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201;
authors.forename: Vinh
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: Research Service, Veteran Affairs Medical Center, Baltimore, MD 21201; Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201; and.
authors.forename: Horea
authors.initials: H
authors.lastname: Rus
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Ching
authors.initials: C
authors.lastname: Chen
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201; Research Service, Veteran Affairs Medical Center, Baltimore, MD 21201; vrus@umaryland.edu.
authors.forename: Violeta
authors.initials: V
authors.lastname: Rus
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology*; D053738:Interleukin-21 Receptor alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000008:administration & dosage / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000517:prevention & control; D008213:Lymphocyte Activation; D051379:Mice; D008811:Mice, Inbred DBA; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: D001323:Autoantibodies; C508118:Il21r protein, mouse; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D000098546:Interleukin-21