Cellular Mechanisms of Restored β-Cell Tolerance Mediated by Protective Alleles of Idd3 and Idd5
- Emma E. Hamilton-Williams1,
- Jocelyn Cheung1,
- Daniel B. Rainbow2,
- Kara M. Hunter2,
- Linda S. Wicker2 and
- Linda A. Sherman1⇓
- 1Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California
- 2Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
- Corresponding author: Linda A. Sherman, .
L.S.W. and L.A.S. contributed equally to this work.
E.E.H.-W. is currently affiliated with the University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
Type 1 diabetes genes within the interleukin (IL)-2, cytotoxic T-lymphocyte--associated protein 4 (CTLA-4), and natural resistance-associated macrophage protein (NRAMP1) pathways influence development of autoimmune diabetes in humans and NOD mice. In NOD mice, when present together, protective alleles encoding IL-2, Idd3 candidate gene, CTLA-4, NRAMP1, and acetyl-coenzyme A dehydrogenase, long-chain (ACADL) (candidate genes for the Idd5.1, Idd5.2, and Idd5.3 subregions) provide nearly complete diabetes protection. To define where the protective alleles of Idd3 and the Idd5 subregions must be present to protect from diabetes and tolerize islet-specific CD8+ T cells, SCID mice were reconstituted so that the host and lymphocytes expressed various combinations of protective and susceptibility alleles at Idd3 and Idd5. Although protective Idd3 alleles in the lymphocytes and protective Idd5 alleles in the SCID host contributed most significantly to CD8 tolerance, both were required together in both lymphocyte and nonlymphocyte cells to recapitulate the potent diabetes protection observed in intact Idd3/5 mice. We conclude that genetic regions involved in autoimmune disease are not restricted in their influence to individual cell types. Even a single protective gene product, such as IL-2, must be expressed in both the lymphocytes and dendritic cells to exert its full extent of disease protection. These studies highlight the pleiotropic effects of genes that determine autoimmune disease susceptibility.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-0790/-/DC1.
- Received June 9, 2011.
- Accepted October 3, 2011.
- © 2012 by the American Diabetes Association.
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