TLR5-deficiency controls dendritic cell subset development in an autoimmune diabetes-susceptible model
IntroductionThe incidence of the autoimmune disease, type 1 diabetes (T1D), has been increasing worldwide and recent studies have shown that the gut microbiota are associated with modulating susceptibility to T1D. Toll-like receptor 5 (TLR5) recognizes bacterial flagellin and is widely expressed on...
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Frontiers Media S.A.
2024-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1333967/full |
| _version_ | 1797292585009545216 |
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| author | James Alexander Pearson James Alexander Pearson Youjia Hu Jian Peng F. Susan Wong Li Wen |
| author_facet | James Alexander Pearson James Alexander Pearson Youjia Hu Jian Peng F. Susan Wong Li Wen |
| author_sort | James Alexander Pearson |
| collection | DOAJ |
| description | IntroductionThe incidence of the autoimmune disease, type 1 diabetes (T1D), has been increasing worldwide and recent studies have shown that the gut microbiota are associated with modulating susceptibility to T1D. Toll-like receptor 5 (TLR5) recognizes bacterial flagellin and is widely expressed on many cells, including dendritic cells (DCs), which are potent antigen-presenting cells (APCs). TLR5 modulates susceptibility to obesity and alters metabolism through gut microbiota; however, little is known about the role TLR5 plays in autoimmunity, especially in T1D.MethodsTo fill this knowledge gap, we generated a TLR5-deficient non-obese diabetic (NOD) mouse, an animal model of human T1D, for study.ResultsWe found that TLR5-deficiency led to a reduction in CD11c+ DC development in utero, prior to microbial colonization, which was maintained into adulthood. This was associated with a bias in the DC populations expressing CD103, with or without CD8α co-expression, and hyper-secretion of different cytokines, both in vitro (after stimulation) and directly ex vivo. We also found that TLR5-deficient DCs were able to promote polyclonal and islet antigen-specific CD4+ T cell proliferation and proinflammatory cytokine secretion. Interestingly, only older TLR5-deficient NOD mice had a greater risk of developing spontaneous T1D compared to wild-type mice.DiscussionIn summary, our data show that TLR5 modulates DC development and enhances cytokine secretion and diabetogenic CD4+ T cell responses. Further investigation into the role of TLR5 in DC development and autoimmune diabetes may give additional insights into the pathogenesis of Type 1 diabetes. |
| first_indexed | 2024-03-07T19:58:35Z |
| format | Article |
| id | doaj.art-f49d25e268f04923a01b31f47da686c0 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-07T19:58:35Z |
| publishDate | 2024-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-f49d25e268f04923a01b31f47da686c02024-02-28T12:21:50ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-02-011510.3389/fimmu.2024.13339671333967TLR5-deficiency controls dendritic cell subset development in an autoimmune diabetes-susceptible modelJames Alexander Pearson0James Alexander Pearson1Youjia Hu2Jian Peng3F. Susan Wong4Li Wen5Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, United StatesDiabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United KingdomSection of Endocrinology, School of Medicine, Yale University, New Haven, CT, United StatesSection of Endocrinology, School of Medicine, Yale University, New Haven, CT, United StatesDiabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United KingdomSection of Endocrinology, School of Medicine, Yale University, New Haven, CT, United StatesIntroductionThe incidence of the autoimmune disease, type 1 diabetes (T1D), has been increasing worldwide and recent studies have shown that the gut microbiota are associated with modulating susceptibility to T1D. Toll-like receptor 5 (TLR5) recognizes bacterial flagellin and is widely expressed on many cells, including dendritic cells (DCs), which are potent antigen-presenting cells (APCs). TLR5 modulates susceptibility to obesity and alters metabolism through gut microbiota; however, little is known about the role TLR5 plays in autoimmunity, especially in T1D.MethodsTo fill this knowledge gap, we generated a TLR5-deficient non-obese diabetic (NOD) mouse, an animal model of human T1D, for study.ResultsWe found that TLR5-deficiency led to a reduction in CD11c+ DC development in utero, prior to microbial colonization, which was maintained into adulthood. This was associated with a bias in the DC populations expressing CD103, with or without CD8α co-expression, and hyper-secretion of different cytokines, both in vitro (after stimulation) and directly ex vivo. We also found that TLR5-deficient DCs were able to promote polyclonal and islet antigen-specific CD4+ T cell proliferation and proinflammatory cytokine secretion. Interestingly, only older TLR5-deficient NOD mice had a greater risk of developing spontaneous T1D compared to wild-type mice.DiscussionIn summary, our data show that TLR5 modulates DC development and enhances cytokine secretion and diabetogenic CD4+ T cell responses. Further investigation into the role of TLR5 in DC development and autoimmune diabetes may give additional insights into the pathogenesis of Type 1 diabetes.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1333967/fullTLR5NOD micedendritic cellstype 1 diabetesmicrobiota |
| spellingShingle | James Alexander Pearson James Alexander Pearson Youjia Hu Jian Peng F. Susan Wong Li Wen TLR5-deficiency controls dendritic cell subset development in an autoimmune diabetes-susceptible model Frontiers in Immunology TLR5 NOD mice dendritic cells type 1 diabetes microbiota |
| title | TLR5-deficiency controls dendritic cell subset development in an autoimmune diabetes-susceptible model |
| title_full | TLR5-deficiency controls dendritic cell subset development in an autoimmune diabetes-susceptible model |
| title_fullStr | TLR5-deficiency controls dendritic cell subset development in an autoimmune diabetes-susceptible model |
| title_full_unstemmed | TLR5-deficiency controls dendritic cell subset development in an autoimmune diabetes-susceptible model |
| title_short | TLR5-deficiency controls dendritic cell subset development in an autoimmune diabetes-susceptible model |
| title_sort | tlr5 deficiency controls dendritic cell subset development in an autoimmune diabetes susceptible model |
| topic | TLR5 NOD mice dendritic cells type 1 diabetes microbiota |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1333967/full |
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