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TSLP and TSLP-conditioned dendritic cells induce Treg differentiation and protection of NOD mice against diabetes

Department of Pediatric, Immunology division, Centre de Recherche Clinique, Faculty of Medicine and Health Sciences, University of Sherbrooke, 3001-12^th Avenue North, Sherbrooke, Quebec, Canada, J1H 5N4

Objective: Autoimmune diabetes in the Non Obese Diabetic (NOD) mouse model results from a breakdown of T cell tolerance caused by impaired tolerogenic dendritic cells development and regulatory T cells (Tregs) differentiation. Re-establishment of the Tregs pool has been shown to confer T cell tolerance and protection against diabetes. Here, we have investigated whether murine Thymic Stromal Lymphopoietin (TSLP) re-established tolerogenic function of DCs and induced differentiation and/or expansion of Tregs in NOD mice and protection against diabetes.

Research Design and Methods: We examined the phenotype of TSLP-conditioned bone marrow DCs (TSLP-DCs) of NOD mice and their functions to induce non-inflammatory Th2 response and differentiation of Treg. The functional relevance of TSLP and TSLP-DCs to development of diabetes was also tested.

Results: Our results showed that bone marrow DCs of NOD mice cultured in the presence of TSLP acquired signatures of tolerogenic DCs such as an absence of production of proinflammatory cytokines and a decreased expression of DCs costimulatory molecules (CD80, CD86, MHC class II) as compared to LPS-treated DCs. Furthermore, TSLP-DCs promoted non-inflammatory Th2 response and induced the conversion of naïve T cells into functional CD4⁺CD25⁺Foxp3⁺ Tregs. We further showed that subcutaneous injections of TSLP for 6 days or a single intravenous injection of TSLP-DCs protected NOD mice against diabetes.

Conclusions: Our study demonstrates that TSLP re-established a tolerogenic immune response in NOD mice and protects from diabetes suggesting that TSLP may have a therapeutic potential for the treatment of type 1 diabetes.

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