Cargando…
TLR2- and Dectin 1–Associated Innate Immune Response Modulates T-Cell Response to Pancreatic β-Cell Antigen and Prevents Type 1 Diabetes
The progression of autoimmune diseases is dictated by deviations in the fine balance between proinflammatory versus regulatory responses, and pathogen recognition receptors (PRRs) play a key role in maintaining this balance. Previously, we have reported that ligation of Toll-like receptor 2 (TLR2) a...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375080/ https://www.ncbi.nlm.nih.gov/pubmed/25377877 http://dx.doi.org/10.2337/db14-1145 |
_version_ | 1782363586464579584 |
---|---|
author | Karumuthil-Melethil, Subha Sofi, M. Hanief Gudi, Radhika Johnson, Benjamin M. Perez, Nicolas Vasu, Chenthamarakshan |
author_facet | Karumuthil-Melethil, Subha Sofi, M. Hanief Gudi, Radhika Johnson, Benjamin M. Perez, Nicolas Vasu, Chenthamarakshan |
author_sort | Karumuthil-Melethil, Subha |
collection | PubMed |
description | The progression of autoimmune diseases is dictated by deviations in the fine balance between proinflammatory versus regulatory responses, and pathogen recognition receptors (PRRs) play a key role in maintaining this balance. Previously, we have reported that ligation of Toll-like receptor 2 (TLR2) and Dectin 1 on antigen-presenting cells by zymosan results in a regulatory immune response that prevents type 1 diabetes (T1D). Here, we show that TLR2 and Dectin 1 engagement by zymosan promotes regulatory T-cell (Treg) responses against the pancreatic β-cell–specific antigen (Ag). Unlike the TLR4 ligand, bacterial lipopolysaccharide, which induced proinflammatory cytokines and pathogenic T cells, zymosan induced a mixture of pro- and anti-inflammatory factors and Tregs, both in vitro and in vivo. Ag-specific T cells that are activated using zymosan-exposed dendritic cells (DCs) expressed Foxp3 and produced large amounts of IL-10, TGF-β1, and IL-17. NOD mice that received β-cell-Ag–loaded, zymosan-exposed DCs showed delayed hyperglycemia. Injection of NOD mice at the prediabetic age and early hyperglycemic stage with β-cell-Ag, along with zymosan, results in a superior protection of the NOD mice from diabetes as compared with mice that received zymosan alone. This therapeutic effect was associated with increased frequencies of IL-10–, IL-17–, IL-4–, and Foxp3-positive T cells, especially in the pancreatic lymph nodes. These results show that zymosan can be used as an immune regulatory adjuvant for modulating the T-cell response to pancreatic β-cell-Ag and reversing early-stage hyperglycemia in T1D. |
format | Online Article Text |
id | pubmed-4375080 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-43750802016-04-01 TLR2- and Dectin 1–Associated Innate Immune Response Modulates T-Cell Response to Pancreatic β-Cell Antigen and Prevents Type 1 Diabetes Karumuthil-Melethil, Subha Sofi, M. Hanief Gudi, Radhika Johnson, Benjamin M. Perez, Nicolas Vasu, Chenthamarakshan Diabetes Immunology and Transplantation The progression of autoimmune diseases is dictated by deviations in the fine balance between proinflammatory versus regulatory responses, and pathogen recognition receptors (PRRs) play a key role in maintaining this balance. Previously, we have reported that ligation of Toll-like receptor 2 (TLR2) and Dectin 1 on antigen-presenting cells by zymosan results in a regulatory immune response that prevents type 1 diabetes (T1D). Here, we show that TLR2 and Dectin 1 engagement by zymosan promotes regulatory T-cell (Treg) responses against the pancreatic β-cell–specific antigen (Ag). Unlike the TLR4 ligand, bacterial lipopolysaccharide, which induced proinflammatory cytokines and pathogenic T cells, zymosan induced a mixture of pro- and anti-inflammatory factors and Tregs, both in vitro and in vivo. Ag-specific T cells that are activated using zymosan-exposed dendritic cells (DCs) expressed Foxp3 and produced large amounts of IL-10, TGF-β1, and IL-17. NOD mice that received β-cell-Ag–loaded, zymosan-exposed DCs showed delayed hyperglycemia. Injection of NOD mice at the prediabetic age and early hyperglycemic stage with β-cell-Ag, along with zymosan, results in a superior protection of the NOD mice from diabetes as compared with mice that received zymosan alone. This therapeutic effect was associated with increased frequencies of IL-10–, IL-17–, IL-4–, and Foxp3-positive T cells, especially in the pancreatic lymph nodes. These results show that zymosan can be used as an immune regulatory adjuvant for modulating the T-cell response to pancreatic β-cell-Ag and reversing early-stage hyperglycemia in T1D. American Diabetes Association 2015-04 2014-11-04 /pmc/articles/PMC4375080/ /pubmed/25377877 http://dx.doi.org/10.2337/db14-1145 Text en © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. |
spellingShingle | Immunology and Transplantation Karumuthil-Melethil, Subha Sofi, M. Hanief Gudi, Radhika Johnson, Benjamin M. Perez, Nicolas Vasu, Chenthamarakshan TLR2- and Dectin 1–Associated Innate Immune Response Modulates T-Cell Response to Pancreatic β-Cell Antigen and Prevents Type 1 Diabetes |
title | TLR2- and Dectin 1–Associated Innate Immune Response Modulates T-Cell Response to Pancreatic β-Cell Antigen and Prevents Type 1 Diabetes |
title_full | TLR2- and Dectin 1–Associated Innate Immune Response Modulates T-Cell Response to Pancreatic β-Cell Antigen and Prevents Type 1 Diabetes |
title_fullStr | TLR2- and Dectin 1–Associated Innate Immune Response Modulates T-Cell Response to Pancreatic β-Cell Antigen and Prevents Type 1 Diabetes |
title_full_unstemmed | TLR2- and Dectin 1–Associated Innate Immune Response Modulates T-Cell Response to Pancreatic β-Cell Antigen and Prevents Type 1 Diabetes |
title_short | TLR2- and Dectin 1–Associated Innate Immune Response Modulates T-Cell Response to Pancreatic β-Cell Antigen and Prevents Type 1 Diabetes |
title_sort | tlr2- and dectin 1–associated innate immune response modulates t-cell response to pancreatic β-cell antigen and prevents type 1 diabetes |
topic | Immunology and Transplantation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375080/ https://www.ncbi.nlm.nih.gov/pubmed/25377877 http://dx.doi.org/10.2337/db14-1145 |
work_keys_str_mv | AT karumuthilmelethilsubha tlr2anddectin1associatedinnateimmuneresponsemodulatestcellresponsetopancreaticbcellantigenandpreventstype1diabetes AT sofimhanief tlr2anddectin1associatedinnateimmuneresponsemodulatestcellresponsetopancreaticbcellantigenandpreventstype1diabetes AT gudiradhika tlr2anddectin1associatedinnateimmuneresponsemodulatestcellresponsetopancreaticbcellantigenandpreventstype1diabetes AT johnsonbenjaminm tlr2anddectin1associatedinnateimmuneresponsemodulatestcellresponsetopancreaticbcellantigenandpreventstype1diabetes AT pereznicolas tlr2anddectin1associatedinnateimmuneresponsemodulatestcellresponsetopancreaticbcellantigenandpreventstype1diabetes AT vasuchenthamarakshan tlr2anddectin1associatedinnateimmuneresponsemodulatestcellresponsetopancreaticbcellantigenandpreventstype1diabetes |