TLR-2 Signaling Promotes IL-17A Production in CD4+CD25+Foxp3+ Regulatory Cells during Oropharyngeal Candidiasis
Recent studies show that CD4+CD25+Foxp3+ regulatory cells (Tregs) produce effector cytokines under inflammatory conditions. However, the direct role of microbial agents that serve as toll-like receptor (TLR) ligands in the induction of effector cytokines in Tregs is less clear. Here we show that CD4...
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| Format: | Article |
| Language: | English |
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MDPI AG
2015-03-01
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| Series: | Pathogens |
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| Online Access: | http://www.mdpi.com/2076-0817/4/1/90 |
| _version_ | 1828151807640076288 |
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| author | Natarajan Bhaskaran Samuel Cohen Yifan Zhang Aaron Weinberg Pushpa Pandiyan |
| author_facet | Natarajan Bhaskaran Samuel Cohen Yifan Zhang Aaron Weinberg Pushpa Pandiyan |
| author_sort | Natarajan Bhaskaran |
| collection | DOAJ |
| description | Recent studies show that CD4+CD25+Foxp3+ regulatory cells (Tregs) produce effector cytokines under inflammatory conditions. However, the direct role of microbial agents that serve as toll-like receptor (TLR) ligands in the induction of effector cytokines in Tregs is less clear. Here we show that CD4+Foxp3+Tregs produce the effector cytokine IL-17A during oropharyngeal candidiasis (OPC) and inflammatory bowel disease in a TLR-2/Myd88 signaling dependent manner. TLR-2 ligands promote proliferation in Tregs in the presence and absence of TCR signals and inflammatory cytokines in vitro. The proliferation is directly dependent on TLR-2 expression in Tregs. Consistent with this, Tlr2−/− mice harbor fewer thymically derived Tregs and peripheral Tregs under homeostatic conditions in vivo. However, under Th17 inducing conditions, IL-6 and TLR-2 signaling both in Tregs as well as antigen presenting cells (APC) are critical for maximal ROR-γt and IL-17A up-regulation in Foxp3+ Tregs. The minimal and transient loss of Foxp3 expression and suppressive properties are due to the presence of IL-6 in the milieu, but not the direct effect of TLR-2 signaling in Tregs. Taken together, our data reveal that TLR-2 signaling promotes not only proliferation, but also IL-17A in Tregs, depending on the cytokine milieu. These IL-17A producing Tregs may be relevant in mucosal infections and inflammation. |
| first_indexed | 2024-04-11T22:02:43Z |
| format | Article |
| id | doaj.art-e7d306da248f4dffb51be0bd3b704189 |
| institution | Directory Open Access Journal |
| issn | 2076-0817 |
| language | English |
| last_indexed | 2024-04-11T22:02:43Z |
| publishDate | 2015-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pathogens |
| spelling | doaj.art-e7d306da248f4dffb51be0bd3b7041892022-12-22T04:00:51ZengMDPI AGPathogens2076-08172015-03-01419011010.3390/pathogens4010090pathogens4010090TLR-2 Signaling Promotes IL-17A Production in CD4+CD25+Foxp3+ Regulatory Cells during Oropharyngeal CandidiasisNatarajan Bhaskaran0Samuel Cohen1Yifan Zhang2Aaron Weinberg3Pushpa Pandiyan4Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH 44106, USARecent studies show that CD4+CD25+Foxp3+ regulatory cells (Tregs) produce effector cytokines under inflammatory conditions. However, the direct role of microbial agents that serve as toll-like receptor (TLR) ligands in the induction of effector cytokines in Tregs is less clear. Here we show that CD4+Foxp3+Tregs produce the effector cytokine IL-17A during oropharyngeal candidiasis (OPC) and inflammatory bowel disease in a TLR-2/Myd88 signaling dependent manner. TLR-2 ligands promote proliferation in Tregs in the presence and absence of TCR signals and inflammatory cytokines in vitro. The proliferation is directly dependent on TLR-2 expression in Tregs. Consistent with this, Tlr2−/− mice harbor fewer thymically derived Tregs and peripheral Tregs under homeostatic conditions in vivo. However, under Th17 inducing conditions, IL-6 and TLR-2 signaling both in Tregs as well as antigen presenting cells (APC) are critical for maximal ROR-γt and IL-17A up-regulation in Foxp3+ Tregs. The minimal and transient loss of Foxp3 expression and suppressive properties are due to the presence of IL-6 in the milieu, but not the direct effect of TLR-2 signaling in Tregs. Taken together, our data reveal that TLR-2 signaling promotes not only proliferation, but also IL-17A in Tregs, depending on the cytokine milieu. These IL-17A producing Tregs may be relevant in mucosal infections and inflammation.http://www.mdpi.com/2076-0817/4/1/90TregFoxp3Th17IL-17ATLR ligandsTLR-2Candida albicans IBD |
| spellingShingle | Natarajan Bhaskaran Samuel Cohen Yifan Zhang Aaron Weinberg Pushpa Pandiyan TLR-2 Signaling Promotes IL-17A Production in CD4+CD25+Foxp3+ Regulatory Cells during Oropharyngeal Candidiasis Pathogens Treg Foxp3 Th17 IL-17A TLR ligands TLR-2 Candida albicans IBD |
| title | TLR-2 Signaling Promotes IL-17A Production in CD4+CD25+Foxp3+ Regulatory Cells during Oropharyngeal Candidiasis |
| title_full | TLR-2 Signaling Promotes IL-17A Production in CD4+CD25+Foxp3+ Regulatory Cells during Oropharyngeal Candidiasis |
| title_fullStr | TLR-2 Signaling Promotes IL-17A Production in CD4+CD25+Foxp3+ Regulatory Cells during Oropharyngeal Candidiasis |
| title_full_unstemmed | TLR-2 Signaling Promotes IL-17A Production in CD4+CD25+Foxp3+ Regulatory Cells during Oropharyngeal Candidiasis |
| title_short | TLR-2 Signaling Promotes IL-17A Production in CD4+CD25+Foxp3+ Regulatory Cells during Oropharyngeal Candidiasis |
| title_sort | tlr 2 signaling promotes il 17a production in cd4 cd25 foxp3 regulatory cells during oropharyngeal candidiasis |
| topic | Treg Foxp3 Th17 IL-17A TLR ligands TLR-2 Candida albicans IBD |
| url | http://www.mdpi.com/2076-0817/4/1/90 |
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