title: IL-2 protects lupus-prone mice from multiple end-organ damage by limiting CD4-CD8- IL-17-producing T cells.
abstract: IL-2, a cytokine with pleiotropic effects, is critical for immune cell activation and peripheral tolerance. Although the therapeutic potential of IL-2 has been previously suggested in autoimmune diseases, the mechanisms whereby IL-2 mitigates autoimmunity and prevents organ damage remain unclear. Using an inducible recombinant adeno-associated virus vector, we investigated the effect of low systemic levels of IL-2 in lupus-prone MRL/Fas(lpr/lpr) (MRL/lpr) mice. Treatment of mice after the onset of disease with IL-2-recombinant adeno-associated virus resulted in reduced mononuclear cell infiltration and pathology of various tissues, including skin, lungs, and kidneys. In parallel, we noted a significant decrease of IL-17-producing CD3(+)CD4(-)CD8(-) double-negative T cells and an increase in CD4(+)CD25(+)Foxp3(+) immunoregulatory T cells (Treg) in the periphery. We also show that IL-2 can drive double-negative (DN) T cell death through an indirect mechanism. Notably, targeted delivery of IL-2 to CD122(+) cytotoxic lymphocytes effectively reduced the number of DN T cells and lymphadenopathy, whereas selective expansion of Treg by IL-2 had no effect on DN T cells. Collectively, our data suggest that administration of IL-2 to lupus-prone mice protects against end-organ damage and suppresses inflammation by dually limiting IL-17-producing DN T cells and expanding Treg.
authors: Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors: Masayuki
authors: M
authors: Mizui
authors: Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors: Tomohiro
authors: T
authors: Koga
authors: Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors: Linda A
authors: LA
authors: Lieberman
authors: Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors: Jessica
authors: J
authors: Beltran
authors: Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors: Nobuya
authors: N
authors: Yoshida
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; and.
authors: Mark C
authors: MC
authors: Johnson
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors: Roland
authors: R
authors: Tisch
authors: Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; gtsokos@bidmc.harvard.edu.
authors: George C
authors: GC
authors: Tsokos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015704:CD4 Antigens; D016827:CD8 Antigens; D005260:Female; D020381:Interleukin-17 / Q000276:immunology; D007376:Interleukin-2 / Q000494:pharmacology*; D053646:Interleukin-2 Receptor beta Subunit / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D015704:CD4 Antigens; D016827:CD8 Antigens; C508022:Il2rb protein, mouse; D020381:Interleukin-17; D007376:Interleukin-2; D053646:Interleukin-2 Receptor beta Subunit