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Idd9/11 genetic locus regulates diabetogenic activity of CD4 T-cells in nonobese diabetic (NOD) mice. Diabetes 2008 Dec;57(12):3273-80

Date

09/09/2008

Pubmed ID

18776136

Pubmed Central ID

PMC2584133

DOI

10.2337/db08-0767

Scopus ID

2-s2.0-58149358856   18 Citations

Abstract

OBJECTIVE: Although the H2(g7) major histocompatibility complex (MHC) provides the primary pathogenic component, the development of T-cell-mediated autoimmune type 1 diabetes in NOD mice also requires contributions from other susceptibility (Idd) genes. Despite sharing the H2(g7) MHC, the closely NOD-related NOR strain remains type 1 diabetes resistant because of contributions of protective Idd5.2, Idd9/11, and Idd13 region alleles. To aid their eventual identification, we evaluated cell types in which non-MHC Idd resistance genes in NOR mice exert disease-protective effects.

RESEARCH DESIGN AND METHODS: Adoptive transfer and bone marrow chimerism approaches tested the diabetogenic activity of CD4 and CD8 T-cells from NOR mice and NOD stocks congenic for NOR-derived Idd resistance loci. Tetramer staining and mimotope stimulation tested the frequency and proliferative capacity of CD4 BDC2.5-like cells. Regulatory T-cells (Tregs) were identified by Foxp3 staining and functionally assessed by in vitro suppression assays.

RESULTS: NOR CD4 T-cells were less diabetogenic than those from NOD mice. The failure of NOR CD4 T-cells to induce type 1 diabetes was not due to decreased proliferative capacity of BDC2.5 clonotypic-like cells. The frequency and function of Tregs in NOD and NOR mice were also equivalent. However, bone marrow chimerism experiments demonstrated that intrinsic factors inhibited the pathogenic activity of NOR CD4 T-cells. The NOR Idd9/11 resistance region on chromosome 4 was found to diminish the diabetogenic activity of CD4 but not CD8 T-cells.

CONCLUSIONS: In conclusion, we demonstrated that a gene(s) within the Idd9/11 region regulates the diabetogenic activity of CD4 T-cells.

Author List

Chen YG, Scheuplein F, Osborne MA, Tsaih SW, Chapman HD, Serreze DV

Authors

Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin
Shirng-Wern Tsaih Research Scientist II in the Obstetrics and Gynecology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antigen-Presenting Cells
CD4-Positive T-Lymphocytes
CD8 Antigens
CD8-Positive T-Lymphocytes
Chromosome Mapping
Diabetes Mellitus, Type 1
Genetic Predisposition to Disease
Major Histocompatibility Complex
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, SCID
Receptors, Antigen, T-Cell, alpha-beta
T-Lymphocyte Subsets
T-Lymphocytes, Regulatory