Idd9.1 locus controls the suppressive activity of FoxP3+CD4+CD25+ regulatory T-cells.
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.
Yamanouchi
Jun
J
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.
Puertas
Maria-Carmen
MC
Verdaguer
Joan
J
Lyons
Paul A
PA
Rainbow
Daniel B
DB
Chamberlain
Giselle
G
Hunter
Kara M
KM
Peterson
Laurence B
LB
Wicker
Linda S
LS
Santamaria
Pere
P
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*
D015704:CD4 Antigens; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D005952:Glucose-6-Phosphatase