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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

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

Address correspondence and reprint requests to Pascale Alard, Department of Microbiology and Immunology, University of Louisville, 319 Abraham Flexner Way, Bldg. 55A, Rm. 405, Louisville, KY 40202. E-mail: p0alar01{at}gwise.louisville.edu

Abbreviations: APC, antigen-presenting cell; CTLA-4, cytotoxic T-lymphocyte–associated antigen-4; Foxp3, Forkhead box P3; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GITR, glucocorticoid-induced tumor necrosis factor receptor; PE, phycoethrin; PerCP, peridinin chlorophyll protein

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.

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