Deficiency in NOD Antigen-Presenting Cell Function May Be Responsible for Suboptimal CD4+CD25+ T-Cell–Mediated Regulation and Type 1 Diabetes Development in NOD Mice

Author:

Alard Pascale1,Manirarora Jean N.1,Parnell Sarah A.1,Hudkins Jason L.1,Clark Sherry L.1,Kosiewicz Michele M.1

Affiliation:

1. From the Department of Microbiology and Immunology, Health Sciences Center, University of Louisville, Louisville, Kentucky

Abstract

Various defects in antigen-presenting cells (APCs) and T-cells, including regulatory cells, have been associated with type 1 diabetes development in NOD mice. CD4+CD25+ regulatory cells play a crucial role in controlling various autoimmune diseases, and a deficiency in their number or function could be involved in disease development. The current study shows that NOD mice had fewer CD4+CD25+ regulatory cells, which expressed normal levels of glucocorticoid-induced tumor necrosis factor receptor and cytotoxic T-lymphocyte–associated antigen-4. We have also found that NOD CD4+CD25+ cells regulate poorly in vitro after stimulation with anti-CD3 and NOD APCs in comparison with B6 CD4+CD25+ cells stimulated with B6 APCs. Surprisingly, stimulation of NOD CD4+CD25+ cells with B6 APCs restored regulation, whereas with the reciprocal combination, NOD APCs failed to activate B6 CD4+CD25+ cells properly. Interestingly, APCs from disease-free (>30 weeks of age), but not diabetic, NOD mice were able to activate CD4+CD25+ regulatory function in vitro and apparently in vivo because only spleens of disease-free NOD mice contained potent CD4+CD25+ regulatory cells that prevented disease development when transferred into young NOD recipients. These data suggest that the failure of NOD APCs to activate CD4+CD25+ regulatory cells may play an important role in controlling type 1 diabetes development in NOD mice.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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