| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
-Mediated CD8+ T Cell Aggression Toward 
Cells in Type 1 Diabetes1
* Cambridge Institute for Medical Research,
Department of Pathology and Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, and
Department of Medical Genetics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom
Identification of candidate genes and their immunological mechanisms that control autoaggressive T cells in inflamed environments, may lead to novel therapies for autoimmune diseases, like type 1 diabetes (T1D). In this study, we used transgenic NOD mice that constitutively express TNF-
in their islets from neonatal life (TNF--NOD) to identify protective alleles that control T1D in the presence of a proinflammatory environment. We show that TNF--mediated breakdown in T cell tolerance requires recessive NOD alleles. To identify some of these recessive alleles, we crossed TNF--NOD mice to diabetes-resistant congenic NOD mice having protective alleles at insulin-dependent diabetes (Idd) loci that control spontaneous T1D at either the preinsulitis (Idd3.Idd5) or postinsulitis (Idd9) phases. No protection from TNF--accelerated T1D was afforded by resistance alleles at Idd3.Idd5. Lack of protection was not at the level of T cell priming, the efficacy of islet-infiltrating APCs to present islet peptides, nor the ability of high levels of CD4+Foxp3+ T cells to accumulate in the islets. In contrast, protective alleles at Idd9 significantly increased the age at which TNF--NOD mice developed T1D. Disease delay was associated with a decreased ability of CD8+ T cells to respond to islet Ags presented by islet-infiltrating APCs. Finally, we demonstrate that the protective region on chromosome 4 that controls T1D in TNF--Idd9 mice is restricted to the Idd9.1 region. These data provide new evidence of the mechanisms by which selective genetic loci control autoimmune diseases in the presence of a strong inflammatory assault.
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 This work was supported with grants from the Juvenile Diabetes Research Foundation and the Wellcome Trust (to E.A.G. and L.S.W.). The availability of NOD congenic mice through the Taconic Farms Emerging Models Program has been supported by grants from the Merck Genome Research Institute, National Institute of Allergy and Infectious Diseases, and the Juvenile Diabetes Research Foundation. E.A.G. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science.
2 Address correspondence and reprint requests to Dr. E. Allison Green, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2XY, U.K. E-mail address: allison.green{at}cimr.cam.ac.uk
3 Abbreviations used in this paper: T1D, type 1 diabetes; PLN, pancreatic lymph node; Idd, insulin-dependent diabetes; Treg, T regulatory.
This article has been cited by other articles:
|
|
 |
|
  G. M. Brodie, M. Wallberg, P. Santamaria, F. S. Wong, and E. A. Green B-Cells Promote Intra-Islet CD8+ Cytotoxic T-Cell Survival to Enhance Type 1 Diabetes Diabetes, April 1, 2008; 57(4): 909 - 917. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
