Besin Gilles, Gaudreau Simon, Ménard Michaël, Guindi Chantal, Dupuis Gilles, Amrani Abdelaziz
Department of Pediatric, Immunology Division, Centre de Recherche Clinique, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada.
Diabetes. 2008 Aug;57(8):2107-17. doi: 10.2337/db08-0171. Epub 2008 May 13.
Autoimmune diabetes in the nonobese diabetic (NOD) mouse model results from a breakdown of T-cell tolerance caused by impaired tolerogenic dendritic cell development and regulatory T-cell (Treg) differentiation. Re-establishment of the Treg 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 dendritic cells and induced differentiation and/or expansion of Tregs in NOD mice and protection against diabetes.
We examined the phenotype of TSLP-conditioned bone marrow dendritic cells (TSLP-DCs) of NOD mice and their functions to induce noninflammatory Th2 response and differentiation of Tregs. The functional relevance of TSLP and TSLP-DCs to development of diabetes was also tested.
Our results showed that bone marrow dendritic cells of NOD mice cultured in the presence of TSLP acquired signatures of tolerogenic dendritic cells, such as an absence of production of pro-inflammatory cytokines and a decreased expression of dendritic cell costimulatory molecules (CD80, CD86, and major histocompatibility complex class II) compared with LPS-treated dendritic cells. Furthermore, TSLP-DCs promoted noninflammatory 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.
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.
非肥胖糖尿病（NOD）小鼠模型中的自身免疫性糖尿病是由致耐受性树突状细胞发育受损和调节性T细胞（Treg）分化障碍导致的T细胞耐受性破坏所引起。已证明重建Treg库可赋予T细胞耐受性并预防糖尿病。在此，我们研究了小鼠胸腺基质淋巴细胞生成素（TSLP）是否能在NOD小鼠中重建树突状细胞的致耐受性功能，诱导Treg的分化和/或扩增，并预防糖尿病。
我们检测了NOD小鼠经TSLP处理的骨髓树突状细胞（TSLP-DCs）的表型及其诱导非炎性Th2反应和Treg分化的功能。还测试了TSLP和TSLP-DCs与糖尿病发生发展的功能相关性。
我们的结果表明，与经脂多糖（LPS）处理的树突状细胞相比，在TSLP存在下培养的NOD小鼠骨髓树突状细胞具有致耐受性树突状细胞的特征，如不产生促炎细胞因子以及树突状细胞共刺激分子（CD80、CD86和主要组织相容性复合体II类）的表达降低。此外，TSLP-DCs促进非炎性Th2反应，并诱导幼稚T细胞转化为功能性CD4(+)CD25(+)Foxp3(+) Tregs。我们进一步表明，皮下注射TSLP 6天或单次静脉注射TSLP-DCs可保护NOD小鼠免受糖尿病侵害。
我们的研究表明，TSLP在NOD小鼠中重建了致耐受性免疫反应并预防糖尿病，这表明TSLP可能具有治疗1型糖尿病的潜力。
