title: Idd9.1 locus controls the suppressive activity of FoxP3+CD4+CD25+ regulatory T-cells.
abstract: OBJECTIVE
  The approximately 45-cM insulin-dependent diabetes 9 (Idd9) region on mouse chromosome 4 harbors several different type 1 diabetes-associated loci. Nonobese diabetic (NOD) mice congenic for the Idd9 region of C57BL/10 (B10) mice, carrying antidiabetogenic alleles in three different Idd9 subregions (Idd9.1, Idd9.2, and Idd9.3), are strongly resistant to type 1 diabetes. However, the mechanisms remain unclear. This study aimed to define mechanisms underlying the type 1 diabetes resistance afforded by B10 Idd9.1, Idd9.2, and/or Idd9.3.
  
  
  METHODS
  We used a reductionist approach that involves comparing the fate of a type 1 diabetes-relevant autoreactive CD8(+) T-cell population, specific for residues 206-214 of islet-specific glucose 6 phosphatase catalytic subunit-related protein (IGRP(206-214)), in noncongenic versus B10 Idd9-congenic (Idd9.1 + Idd9.2 + Idd9.3, Idd9.2 + Idd9.3, Idd9.1, Idd9.2, and Idd9.3) T-cell receptor (TCR)-transgenic (8.3) NOD mice.
  
  
  RESULTS
  Most of the protective effect of Idd9 against 8.3-CD8(+) T-cell-enhanced type 1 diabetes was mediated by Idd9.1. Although Idd9.2 and Idd9.3 afforded some protection, the effects were small and did not enhance the greater protective effect of Idd9.1. B10 Idd9.1 afforded type 1 diabetes resistance without impairing the developmental biology or intrinsic diabetogenic potential of autoreactive CD8(+) T-cells. Studies in T- and B-cell-deficient 8.3-NOD.B10 Idd9.1 mice revealed that this antidiabetogenic effect was mediated by endogenous, nontransgenic T-cells in a B-cell-independent manner. Consistent with this, B10 Idd9.1 increased the suppressive function and antidiabetogenic activity of the FoxP3(+)CD4(+)CD25(+) T-cell subset in both TCR-transgenic and nontransgenic mice.
  
  
  CONCLUSIONS
  A gene(s) within Idd9.1 regulates the development and function of FoxP3(+)CD4(+)CD25(+) regulatory T-cells and, in turn, the activation of CD8(+) effector T-cells in the pancreatic draining lymph nodes, without affecting their development or intrinsic diabetogenic potential.
authors.affiliation: Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology and Infectious Diseases, Institute for Infection, Immunity and Inflammation, Faculty of Medicine, The University of Calgary, Calgary, Alberta, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Yamanouchi
authors.forename: Maria-Carmen
authors.initials: MC
authors.lastname: Puertas
authors.forename: Joan
authors.initials: J
authors.lastname: Verdaguer
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lyons
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Rainbow
authors.forename: Giselle
authors.initials: G
authors.lastname: Chamberlain
authors.forename: Kara M
authors.initials: KM
authors.lastname: Hunter
authors.forename: Laurence B
authors.initials: LB
authors.lastname: Peterson
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wicker
authors.forename: Pere
authors.initials: P
authors.lastname: Santamaria
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D002874:Chromosome Mapping; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D005952:Glucose-6-Phosphatase / Q000235:genetics; D007165:Immunosuppression Therapy; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D016688:Mice, Inbred NOD / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D005952:Glucose-6-Phosphatase