Idd9.2 and Idd9.3 Protective Alleles Function in CD4(+) T-Cells and Nonlymphoid Cells to Prevent Expansion of Pathogenic Islet-Specific CD8(+) T-Cells

Hamilton-Williams, Emma E., Wong, S.B. Justin, Martinez, Xavier, Rainbow, Daniel B., Hunter, Kara M., Wicker, Linda S. and Sherman, Linda A. (2010) Idd9.2 and Idd9.3 Protective Alleles Function in CD4(+) T-Cells and Nonlymphoid Cells to Prevent Expansion of Pathogenic Islet-Specific CD8(+) T-Cells. Diabetes, 59 6: 1478-1486. doi:10.2337/db09-1801


Author Hamilton-Williams, Emma E.
Wong, S.B. Justin
Martinez, Xavier
Rainbow, Daniel B.
Hunter, Kara M.
Wicker, Linda S.
Sherman, Linda A.
Title Idd9.2 and Idd9.3 Protective Alleles Function in CD4(+) T-Cells and Nonlymphoid Cells to Prevent Expansion of Pathogenic Islet-Specific CD8(+) T-Cells
Journal name Diabetes   Check publisher's open access policy
ISSN 0012-1797
1939-327X
Publication date 2010-06
Sub-type Article (original research)
DOI 10.2337/db09-1801
Volume 59
Issue 6
Start page 1478
End page 1486
Total pages 9
Place of publication Alexandria, VA, United States
Publisher American Diabetes Association
Language eng
Formatted abstract
OBJECTIVE -
Multiple type 1 diabetes susceptibility genes have now been identified in both humans and mice, yet mechanistic understanding of how they impact disease pathogenesis is still minimal. We have sought to dissect the cellular basis for how the highly protective mouse Idd9 region limits the expansion of autoreactive CD8+ T-cells, a key cell type in destruction of the islets.

RESEARCH DESIGN AND METHODS -
We assess the endogenous CD8+ T-cell repertoire for reactivity to the islet antigen glucose-6-phosphatase-related protein (IGRP). Through the use of adoptively transferred T-cells, bone marrow chimeras, and reconstituted severe combined immunodeficient mice, we identify the protective cell types involved.

RESULTS -
IGRP-specific CD8+ T-cells are present at low frequency in the insulitic lesions of Idd9 mice and could not be recalled in the periphery by viral expansion. We show that Idd9 genes act extrinsically to the CD8 + T-cell to prevent the massive expansion of pathogenic effectors near the time of disease onset that occurs in NOD mice. The subregions Idd9.2 and Idd9.3 mediated this effect. Interestingly, the Idd9.1 region, which provides significant protection from disease, did not prevent the expansion of autoreactive CD8+ T-cells. Expression of Idd9 genes was required by both CD4+ T-cells and a nonlymphoid cell to induce optimal tolerance.

CONCLUSIONS -
Idd9 protective alleles are associated with reduced expansion of IGRP-specific CD8+ T-cells. Intrinsic expression of protective Idd9 alleles in CD4+ T-cells and nonlymphoid cells is required to achieve an optimal level of tolerance. Protective alleles in the Idd9.2 congenic subregion are required for the maximal reduction of islet-specific CD8 + T-cells.
Keyword Nonobese Diabetic Mice
Nod Mice
Dendritic Cells
Congenic Mice
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: ERA 2012 Admin Only
UQ Diamantina Institute Publications
 
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