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Idd9.1 Locus Controls the Suppressive Activity of FoxP3(+)CD4(+)CD25(+) Regulatory T-Cells

OBJECTIVE: The ∼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 (Id...

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Autores principales: Yamanouchi, Jun, Puertas, Maria-Carmen, Verdaguer, Joan, Lyons, Paul A., Rainbow, Daniel B., Chamberlain, Giselle, Hunter, Kara M., Peterson, Laurence B., Wicker, Linda S., Santamaria, Pere
Formato: Texto
Lenguaje:English
Publicado: American Diabetes Association 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797933/
https://www.ncbi.nlm.nih.gov/pubmed/19833887
http://dx.doi.org/10.2337/db09-0648
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author Yamanouchi, Jun
Puertas, Maria-Carmen
Verdaguer, Joan
Lyons, Paul A.
Rainbow, Daniel B.
Chamberlain, Giselle
Hunter, Kara M.
Peterson, Laurence B.
Wicker, Linda S.
Santamaria, Pere
author_facet Yamanouchi, Jun
Puertas, Maria-Carmen
Verdaguer, Joan
Lyons, Paul A.
Rainbow, Daniel B.
Chamberlain, Giselle
Hunter, Kara M.
Peterson, Laurence B.
Wicker, Linda S.
Santamaria, Pere
author_sort Yamanouchi, Jun
collection PubMed
description OBJECTIVE: The ∼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. RESEARCH DESIGN AND 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.
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spelling pubmed-27979332011-01-01 Idd9.1 Locus Controls the Suppressive Activity of FoxP3(+)CD4(+)CD25(+) Regulatory T-Cells Yamanouchi, Jun Puertas, Maria-Carmen Verdaguer, Joan Lyons, Paul A. Rainbow, Daniel B. Chamberlain, Giselle Hunter, Kara M. Peterson, Laurence B. Wicker, Linda S. Santamaria, Pere Diabetes Original Article OBJECTIVE: The ∼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. RESEARCH DESIGN AND 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. American Diabetes Association 2010-01 2009-10-15 /pmc/articles/PMC2797933/ /pubmed/19833887 http://dx.doi.org/10.2337/db09-0648 Text en © 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Original Article
Yamanouchi, Jun
Puertas, Maria-Carmen
Verdaguer, Joan
Lyons, Paul A.
Rainbow, Daniel B.
Chamberlain, Giselle
Hunter, Kara M.
Peterson, Laurence B.
Wicker, Linda S.
Santamaria, Pere
Idd9.1 Locus Controls the Suppressive Activity of FoxP3(+)CD4(+)CD25(+) Regulatory T-Cells
title Idd9.1 Locus Controls the Suppressive Activity of FoxP3(+)CD4(+)CD25(+) Regulatory T-Cells
title_full Idd9.1 Locus Controls the Suppressive Activity of FoxP3(+)CD4(+)CD25(+) Regulatory T-Cells
title_fullStr Idd9.1 Locus Controls the Suppressive Activity of FoxP3(+)CD4(+)CD25(+) Regulatory T-Cells
title_full_unstemmed Idd9.1 Locus Controls the Suppressive Activity of FoxP3(+)CD4(+)CD25(+) Regulatory T-Cells
title_short Idd9.1 Locus Controls the Suppressive Activity of FoxP3(+)CD4(+)CD25(+) Regulatory T-Cells
title_sort idd9.1 locus controls the suppressive activity of foxp3(+)cd4(+)cd25(+) regulatory t-cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797933/
https://www.ncbi.nlm.nih.gov/pubmed/19833887
http://dx.doi.org/10.2337/db09-0648
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