| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Microbiology and Immunology, and McGill Center for the Study of Host Resistance, McGill University, Montreal, Québec, Canada
Type I diabetes (T1D) susceptibility is inherited through multiple insulin-dependent diabetes (Idd) genes. NOD.B6 Idd3 congenic mice, introgressed with an Idd3 allele from T1D-resistant C57BL/6 mice (Idd3B6), show a marked resistance to T1D compared with control NOD mice. The protective function of the Idd3 locus is confined to the Il2 gene, whose expression is critical for naturally occurring CD4+Foxp3+ regulatory T (nTreg) cell development and function. In this study, we asked whether Idd3B6 protective alleles in the NOD mouse model confer T1D resistance by promoting the cellular frequency, function, or homeostasis of nTreg cells in vivo. We show that resistance to T1D in NOD.B6 Idd3 congenic mice correlates with increased levels of IL-2 mRNA and protein production in Ag-activated diabetogenic CD4+ T cells. We also observe that protective IL2 allelic variants (Idd3B6 resistance allele) also favor the expansion and suppressive functions of CD4+Foxp3+ nTreg cells in vitro, as well as restrain the proliferation, IL-17 production, and pathogenicity of diabetogenic CD4+ T cells in vivo more efficiently than control do nTreg cells. Lastly, the resistance to T1D in Idd3 congenic mice does not correlate with an augmented systemic frequency of CD4+Foxp3+ nTreg cells but more so with the ability of protective IL2 allelic variants to promote the expansion of CD4+Foxp3+ nTreg cells directly in the target organ undergoing autoimmune attack. Thus, protective, IL2 allelic variants impinge the development of organ-specific autoimmunity by bolstering the IL-2 producing capacity of self-reactive CD4+ T cells and, in turn, favor the function and homeostasis of CD4+Foxp3+ nTreg cells in vivo.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 We acknowledge the support of the Canadian Institutes for Health Research (MOP 67211) and Canadian Diabetes Association (GA-3–05-1898-CP). A.A. and E.S. are recipients of fellowships from the McGill University Health Centre Research Institute (to A.A. and E.S.) and Canadian Institutes for Health Research training grant in neuroinflammation (to E.S.). C.A.P. is the recipient of the Canada Research Chair.
2 Address correspondence and reprint requests to Dr. Ciriaco A. Piccirillo, Department of Microbiology and Immunology, and Center for the Study of Host Resistance, McGill University, 3775 University Street, Montreal, Québec, Canada H3A 2B4. E-mail address: Ciro.piccirillo{at}mcgill.ca
3 Abbreviations used in this paper: T1D, type 1 diabetes; BMDC, bone marrow-derived dendritic cell; DC, dendritic cell; ICS, intracellular cytokine staining; LN, lymph node; nTreg, naturally occurring regulatory T; pancLN, pancreatic lymph node; Teff, effector T; WT, wild type.
This article has been cited by other articles:
|
|
 |
|
  E. E. Hamilton-Williams, X. Martinez, J. Clark, S. Howlett, K. M. Hunter, D. B. Rainbow, L. Wen, M. J. Shlomchik, J. D. Katz, G. F. Beilhack, et al. Expression of Diabetes-Associated Genes by Dendritic Cells and CD4 T Cells Drives the Loss of Tolerance in Nonobese Diabetic Mice J. Immunol., August 1, 2009; 183(3): 1533 - 1541. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
