title: Singular role for T-BET+CXCR3+ regulatory T cells in protection from autoimmune diabetes.
abstract: Foxp3+regulatory T (Treg) cells are crucial for restraining inflammation in a variety of autoimmune diseases, including type 1 diabetes (T1D). However, the transcriptional and functional phenotypes of Treg cells within the pancreatic lesion remain poorly understood. Here we characterized pancreas-infiltrating Treg cells in the NOD mouse model of T1D and uncovered a substantial enrichment of the Treg subpopulation expressing the chemokine receptor CXCR3. Accumulation of CXCR3+Treg cells within pancreatic islets was dependent on the transcription factor T-BET, and genetic ablation of T-BET increased the onset and penetrance of disease, abrogating the sex bias normally seen in the NOD model. Both male and female mice lacking T-BET+Treg cells showed a more aggressive insulitic infiltrate, reflected most prominently by elevated production of type 1 cytokines. Our results suggest the possibility of fine therapeutic targeting of Treg cells, in a tissue- and cell-subset-specific fashion, as a more focused immunotherapy for T1D.
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
authors.forename: Tze Guan
authors.initials: TG
authors.lastname: Tan
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 cbdm@hms.harvard.edu.
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 cbdm@hms.harvard.edu.
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D008297:Male; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000276:immunology; D054367:Receptors, CXCR3 / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D059467:Transcriptome; D000098815:T-bet Transcription Factor
chemical_list: C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor
keywords: Treg subsets; immunogenomics; immunoregulation