title: Deletion of CD24 impairs development of heat shock protein gp96-driven autoimmune disease through expansion of myeloid-derived suppressor cells.
abstract: CD24 binds to and suppresses inflammation triggered by danger-associated molecular patterns such as heat shock proteins (HSPs) and high-mobility group box 1. Paradoxically, CD24 has been shown to enhance autoimmune disease. In this study, we attempt to reconcile this paradox by deletion of CD24 (24KO) in a lupus-like disease model driven by forced expression of HSP gp96 at the cell surface (transgenic mice [tm]). As expected, tm24KO mice showed increased CD11c(+) dendritic cell activation coupled to a significant increase in dendritic cell-specific IL-12 production compared with tm mice. However, tm24KO mice showed less CD4 T cell activation and peripheral inflammatory cytokine production in comparison with tm mice. We characterized an enhanced immune suppressive milieu in tm24KO mice distinguished by increased TGF-β and greater regulatory T cell-suppressive capacity. We found greater absolute numbers of myeloid-derived suppressor cells (MDSCs) in tm24KO mice and showed that the Ly6C(+) MDSC subset had greater suppressive capacity from tm24KO mice. Deletion of CD24 in tm mice led to diminished lupus-like pathology as evidenced by anti-nuclear Ab deposition and glomerulonephritis. Finally, we show that expanded MDSC populations were mediated by increased free high-mobility group box 1 in tm24KO mice. Thus, the deletion of CD24 in an HSP-driven model of autoimmunity led to the unexpected development of regulatory T cell and MDSC populations that augmented immune tolerance. Further study of these populations as possible negative regulators of inflammation in the context of autoimmunity is warranted.
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Thaxton
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Bei
authors.initials: B
authors.lastname: Liu
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010.
authors.forename: Pan
authors.initials: P
authors.lastname: Zheng
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425; and zihai@musc.edu.
authors.forename: Zihai
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D039521:CD11c Antigen / Q000235:genetics / Q000276:immunology; D051927:CD24 Antigen / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D017353:Gene Deletion; D007108:Immune Tolerance / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology
chemical_list: D039521:CD11c Antigen; D051927:CD24 Antigen; C497890:Cd24a protein, mouse; D008562:Membrane Glycoproteins; D016212:Transforming Growth Factor beta; C053387:endoplasmin