HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Poussier, P. Articles by Ramanathan, S. Search for Related Content PubMed PubMed Citation Articles by Poussier, P. Articles by Ramanathan, S. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Medline Plus Health Information Diabetes

Impaired Post-Thymic Development of Regulatory CD4⁺25⁺ T Cells Contributes to Diabetes Pathogenesis in BB Rats¹

Philippe Poussier^2,*,,, Terri Ning^*,, Trista Murphy^*,, Dominika Dabrowski^*, and Sheela Ramanathan^*,

^* Sunnybrook and Women’s College Health Sciences Centre, and Departments of Immunology and Medicine, University of Toronto, Toronto, Ontario, Canada

One of the BB rat diabetes (diabetes mellitus (DM)) susceptibility genes is an Ian5 mutation resulting in premature apoptosis of naive T cells. Impaired differentiation of regulatory T cells has been suggested as one possible mechanism through which this mutation contributes to antipancreatic autoimmunity. Using Ian5 congenic inbred rats (wild-type (non-lyp BB) and mutated (BB)), we assessed the development of BB regulatory CD8^–4⁺25⁺T cells and their role in the pathogenesis of DM. BB rats have normal numbers of functional CD8^–4⁺25⁺Foxp3⁺ thymocytes. The proportion of CD25⁺ cells among CD8^–4⁺ recent thymic emigrants is also normal while it is increased among more mature CD8^–4⁺ T cells. However, BB CD8^–4⁺25⁺Foxp3⁺ thymocytes fail to undergo homeostatic expansion and survive upon transfer to nude BB rats while Foxp3 expression is reduced in mature CD8^–4⁺25⁺ T cells suggesting that these cells are mostly activated cells. Consistent with this interpretation, peripheral BB CD8^–4⁺25⁺ T cells do not suppress anti-TCR-mediated activation of non-lyp BB CD8^–4⁺25^– T cells but rather stimulate it. Furthermore, adoptive transfer of unfractionated T cells from diabetic BB donors induces DM in 71% of the recipients while no DM occurred when donor T cells are depleted of CD8^–4⁺25⁺ cells. Adoptive transfer of 10⁶ regulatory non-lyp BB CD8^–4⁺25⁺ T cells to young BB rats protects the recipients from DM. Taken together, these results demonstrate that the BB rat Ian5 mutation alters the survival and function of regulatory CD8^–4⁺25⁺ T cells at the post-thymic level, resulting in clonal expansion of diabetogenic T cells among peripheral CD8^–4⁺25⁺ cells.

This article has been cited by other articles:

				M. Lim, D. Sheen, S. Kim, S. Won, S-S Lee, S-C Chae, H-T Chung, and S. Shim IAN5 polymorphisms are associated with systemic lupus erythematosus Lupus, October 1, 2009; 18(12): 1045 - 1052. [Abstract] [PDF]

				I. Hadjiyanni, K. K. Li, and D. J. Drucker Glucagon-Like Peptide-2 Reduces Intestinal Permeability But Does Not Modify the Onset of Type 1 Diabetes in the Nonobese Diabetic Mouse Endocrinology, February 1, 2009; 150(2): 592 - 599. [Abstract] [Full Text] [PDF]

				R. D. Schulteis, H. Chu, X. Dai, Y. Chen, B. Edwards, D. Haribhai, C. B. Williams, S. Malarkannan, M. J. Hessner, S. Glisic-Milosavljevic, et al. Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5 Blood, December 15, 2008; 112(13): 4905 - 4914. [Abstract] [Full Text] [PDF]

				I. Hadjiyanni, L. L. Baggio, P. Poussier, and D. J. Drucker Exendin-4 Modulates Diabetes Onset in Nonobese Diabetic Mice Endocrinology, March 1, 2008; 149(3): 1338 - 1349. [Abstract] [Full Text] [PDF]

				J. M. Fuller, A. E. Kwitek, T. J. Hawkins, D. H. Moralejo, W. Lu, T. D. Tupling, A. J. MacMurray, G. Borchardt, M. Hasinoff, and A. Lernmark Introgression of F344 Rat Genomic DNA on BB Rat Chromosome 4 Generates Diabetes-Resistant Lymphopenic BB Rats Diabetes, December 1, 2006; 55(12): 3351 - 3357. [Abstract] [Full Text] [PDF]

				J.-L. Hillebrands, B. Whalen, J. T. J. Visser, J. Koning, K. D. Bishop, J. Leif, J. Rozing, J. P. Mordes, D. L. Greiner, and A. A. Rossini A Regulatory CD4+ T Cell Subset in the BB Rat Model of Autoimmune Diabetes Expresses Neither CD25 Nor Foxp3 J. Immunol., December 1, 2006; 177(11): 7820 - 7832. [Abstract] [Full Text] [PDF]

				R. Geoffrey, S. Jia, A. E. Kwitek, J. Woodliff, S. Ghosh, A. Lernmark, X. Wang, and M. J. Hessner Evidence of a Functional Role for Mast Cells in the Development of Type 1 Diabetes Mellitus in the BioBreeding Rat J. Immunol., November 15, 2006; 177(10): 7275 - 7286. [Abstract] [Full Text] [PDF]

				D. Tischner, A. Weishaupt, J. v. d. Brandt, N. Muller, N. Beyersdorf, C. W. Ip, K. V. Toyka, T. Hunig, R. Gold, T. Kerkau, et al. Polyclonal expansion of regulatory T cells interferes with effector cell migration in a model of multiple sclerosis Brain, October 1, 2006; 129(10): 2635 - 2647. [Abstract] [Full Text] [PDF]

				O. Saitoh and Y. Nagayama Regulation of Graves' Hyperthyroidism with Naturally Occurring CD4+CD25+ Regulatory T Cells in a Mouse Model Endocrinology, May 1, 2006; 147(5): 2417 - 2422. [Abstract] [Full Text] [PDF]