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Thymic stromal lymphopoietin and thymic stromal lymphopoietin-conditioned dendritic cells induce regulatory T-cell differentiation and protection of NOD mice against diabetes.
Diabetes. 2008 Aug; 57(8):2107-17.D

Abstract

OBJECTIVE

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.

RESEARCH DESIGN AND METHODS

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.

RESULTS

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.

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.

Authors+Show Affiliations

Department of Pediatric, Immunology Division, Centre de Recherche Clinique, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18477807

Citation

Besin, Gilles, et al. "Thymic Stromal Lymphopoietin and Thymic Stromal Lymphopoietin-conditioned Dendritic Cells Induce Regulatory T-cell Differentiation and Protection of NOD Mice Against Diabetes." Diabetes, vol. 57, no. 8, 2008, pp. 2107-17.
Besin G, Gaudreau S, Ménard M, et al. Thymic stromal lymphopoietin and thymic stromal lymphopoietin-conditioned dendritic cells induce regulatory T-cell differentiation and protection of NOD mice against diabetes. Diabetes. 2008;57(8):2107-17.
Besin, G., Gaudreau, S., Ménard, M., Guindi, C., Dupuis, G., & Amrani, A. (2008). Thymic stromal lymphopoietin and thymic stromal lymphopoietin-conditioned dendritic cells induce regulatory T-cell differentiation and protection of NOD mice against diabetes. Diabetes, 57(8), 2107-17. https://doi.org/10.2337/db08-0171
Besin G, et al. Thymic Stromal Lymphopoietin and Thymic Stromal Lymphopoietin-conditioned Dendritic Cells Induce Regulatory T-cell Differentiation and Protection of NOD Mice Against Diabetes. Diabetes. 2008;57(8):2107-17. PubMed PMID: 18477807.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Thymic stromal lymphopoietin and thymic stromal lymphopoietin-conditioned dendritic cells induce regulatory T-cell differentiation and protection of NOD mice against diabetes. AU - Besin,Gilles, AU - Gaudreau,Simon, AU - Ménard,Michaël, AU - Guindi,Chantal, AU - Dupuis,Gilles, AU - Amrani,Abdelaziz, Y1 - 2008/05/13/ PY - 2008/5/15/pubmed PY - 2008/9/5/medline PY - 2008/5/15/entrez SP - 2107 EP - 17 JF - Diabetes JO - Diabetes VL - 57 IS - 8 N2 - OBJECTIVE: 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. RESEARCH DESIGN AND METHODS: 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. RESULTS: 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. 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. SN - 1939-327X UR - https://www.unboundmedicine.com/medline/citation/18477807/Thymic_stromal_lymphopoietin_and_thymic_stromal_lymphopoietin_conditioned_dendritic_cells_induce_regulatory_T_cell_differentiation_and_protection_of_NOD_mice_against_diabetes_ L2 - https://diabetes.diabetesjournals.org/lookup/pmidlookup?view=long&pmid=18477807 DB - PRIME DP - Unbound Medicine ER -