title: DCIR2+ cDC2 DCs and Zbtb32 Restore CD4+ T-Cell Tolerance and Inhibit Diabetes.
abstract: During autoimmunity, the normal ability of dendritic cells (DCs) to induce T-cell tolerance is disrupted; therefore, autoimmune disease therapies based on cell types and molecular pathways that elicit tolerance in the steady state may not be effective. To determine which DC subsets induce tolerance in the context of chronic autoimmunity, we used chimeric antibodies specific for DC inhibitory receptor 2 (DCIR2) or DEC-205 to target self-antigen to CD11b(+) (cDC2) DCs and CD8(+) (cDC1) DCs, respectively, in autoimmune-prone nonobese diabetic (NOD) mice. Antigen presentation by DCIR2(+) DCs but not DEC-205(+) DCs elicited tolerogenic CD4(+) T-cell responses in NOD mice. β-Cell antigen delivered to DCIR2(+) DCs delayed diabetes induction and induced increased T-cell apoptosis without interferon-γ (IFN-γ) or sustained expansion of autoreactive CD4(+) T cells. These divergent responses were preceded by differential gene expression in T cells early after in vivo stimulation. Zbtb32 was higher in T cells stimulated with DCIR2(+) DCs, and overexpression of Zbtb32 in T cells inhibited diabetes development, T-cell expansion, and IFN-γ production. Therefore, we have identified DCIR2(+) DCs as capable of inducing antigen-specific tolerance in the face of ongoing autoimmunity and have also identified Zbtb32 as a suppressive transcription factor that controls T cell-mediated autoimmunity.
authors.affiliation: Immune Tolerance Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Price
authors.affiliation: Immune Tolerance Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Chie
authors.initials: C
authors.lastname: Hotta-Iwamura
authors.affiliation: Immune Tolerance Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Yongge
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Immune Tolerance Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Beauchamp
authors.affiliation: Immune Tolerance Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD tarbellk@niddk.nih.gov.
authors.forename: Kristin V
authors.identifier: http://orcid.org/0000-0003-3738-379X
authors.initials: KV
authors.lastname: Tarbell
mesh_terms: D000818:Animals; D000906:Antibodies; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015551:Autoimmunity / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000502:physiology*; D003920:Diabetes Mellitus / Q000276:immunology* / Q000517:prevention & control; D051858:Forkhead Transcription Factors / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D019013:CD40 Antigens; C000603984:DCIR2 protein, mouse; C093569:DEC-205 receptor; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; C406863:Rog protein, mouse