IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice
Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of insulin-producing β cells. BDC2.5 T cells in BDC2.5 CD4+ T cell receptor transgenic Non-Obese Diabetic (NOD) mice (BDC2.5+ NOD mice) can abruptly invade the pancreatic islets resulting in severe insulitis that progress...
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.702955/full |
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| author | Juan Huang Juan Huang Qiyuan Tan Qiyuan Tan Ningwen Tai James Alexander Pearson James Alexander Pearson Yangyang Li Yangyang Li Chen Chao Lucy Zhang Jian Peng Yanpeng Xing Yanpeng Xing Luyao Zhang Luyao Zhang Youjia Hu Zhiguang Zhou F. Susan Wong Li Wen |
| author_facet | Juan Huang Juan Huang Qiyuan Tan Qiyuan Tan Ningwen Tai James Alexander Pearson James Alexander Pearson Yangyang Li Yangyang Li Chen Chao Lucy Zhang Jian Peng Yanpeng Xing Yanpeng Xing Luyao Zhang Luyao Zhang Youjia Hu Zhiguang Zhou F. Susan Wong Li Wen |
| author_sort | Juan Huang |
| collection | DOAJ |
| description | Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of insulin-producing β cells. BDC2.5 T cells in BDC2.5 CD4+ T cell receptor transgenic Non-Obese Diabetic (NOD) mice (BDC2.5+ NOD mice) can abruptly invade the pancreatic islets resulting in severe insulitis that progresses rapidly but rarely leads to spontaneous diabetes. This prevention of diabetes is mediated by T regulatory (Treg) cells in these mice. In this study, we investigated the role of interleukin 10 (IL-10) in the inhibition of diabetes in BDC2.5+ NOD mice by generating Il-10-deficient BDC2.5+ NOD mice (BDC2.5+Il-10-/- NOD mice). Our results showed that BDC2.5+Il-10-/- NOD mice displayed robust and accelerated diabetes development. Il-10 deficiency in BDC2.5+ NOD mice promoted the generation of neutrophils in the bone marrow and increased the proportions of neutrophils in the periphery (blood, spleen, and islets), accompanied by altered intestinal immunity and gut microbiota composition. In vitro studies showed that the gut microbiota from BDC2.5+Il-10-/- NOD mice can expand neutrophil populations. Moreover, in vivo studies demonstrated that the depletion of endogenous gut microbiota by antibiotic treatment decreased the proportion of neutrophils. Although Il-10 deficiency in BDC2.5+ NOD mice had no obvious effects on the proportion and function of Treg cells, it affected the immune response and activation of CD4+ T cells. Moreover, the pathogenicity of CD4+ T cells was much increased, and this significantly accelerated the development of diabetes when these CD4+ T cells were transferred into immune-deficient NOD mice. Our study provides novel insights into the role of IL-10 in the modulation of neutrophils and CD4+ T cells in BDC2.5+ NOD mice, and suggests important crosstalk between gut microbiota and neutrophils in type 1 diabetes development. |
| first_indexed | 2024-12-16T14:28:54Z |
| format | Article |
| id | doaj.art-cf52e47c5e7241fbb217e4c3376aab03 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-16T14:28:54Z |
| publishDate | 2021-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-cf52e47c5e7241fbb217e4c3376aab032022-12-21T22:28:17ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-07-011210.3389/fimmu.2021.702955702955IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD MiceJuan Huang0Juan Huang1Qiyuan Tan2Qiyuan Tan3Ningwen Tai4James Alexander Pearson5James Alexander Pearson6Yangyang Li7Yangyang Li8Chen Chao9Lucy Zhang10Jian Peng11Yanpeng Xing12Yanpeng Xing13Luyao Zhang14Luyao Zhang15Youjia Hu16Zhiguang Zhou17F. Susan Wong18Li Wen19National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, ChinaSection of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, United StatesSection of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, United StatesDepartment of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai, ChinaSection of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, United StatesSection of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, United StatesDivision of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United KingdomSection of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, United StatesDepartment of Endocrinology, The Second Hospital of Jilin University, Changchun, ChinaNational Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, ChinaSection of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, United StatesSection of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, United StatesSection of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, United StatesDepartment of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, ChinaSection of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, United StatesDepartment of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, ChinaSection of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, United StatesNational Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, ChinaDivision of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United KingdomSection of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, United StatesType 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of insulin-producing β cells. BDC2.5 T cells in BDC2.5 CD4+ T cell receptor transgenic Non-Obese Diabetic (NOD) mice (BDC2.5+ NOD mice) can abruptly invade the pancreatic islets resulting in severe insulitis that progresses rapidly but rarely leads to spontaneous diabetes. This prevention of diabetes is mediated by T regulatory (Treg) cells in these mice. In this study, we investigated the role of interleukin 10 (IL-10) in the inhibition of diabetes in BDC2.5+ NOD mice by generating Il-10-deficient BDC2.5+ NOD mice (BDC2.5+Il-10-/- NOD mice). Our results showed that BDC2.5+Il-10-/- NOD mice displayed robust and accelerated diabetes development. Il-10 deficiency in BDC2.5+ NOD mice promoted the generation of neutrophils in the bone marrow and increased the proportions of neutrophils in the periphery (blood, spleen, and islets), accompanied by altered intestinal immunity and gut microbiota composition. In vitro studies showed that the gut microbiota from BDC2.5+Il-10-/- NOD mice can expand neutrophil populations. Moreover, in vivo studies demonstrated that the depletion of endogenous gut microbiota by antibiotic treatment decreased the proportion of neutrophils. Although Il-10 deficiency in BDC2.5+ NOD mice had no obvious effects on the proportion and function of Treg cells, it affected the immune response and activation of CD4+ T cells. Moreover, the pathogenicity of CD4+ T cells was much increased, and this significantly accelerated the development of diabetes when these CD4+ T cells were transferred into immune-deficient NOD mice. Our study provides novel insights into the role of IL-10 in the modulation of neutrophils and CD4+ T cells in BDC2.5+ NOD mice, and suggests important crosstalk between gut microbiota and neutrophils in type 1 diabetes development.https://www.frontiersin.org/articles/10.3389/fimmu.2021.702955/fulltype 1 diabetesinterleukin-10neutrophilsgut microbiotaCD4+ T cells |
| spellingShingle | Juan Huang Juan Huang Qiyuan Tan Qiyuan Tan Ningwen Tai James Alexander Pearson James Alexander Pearson Yangyang Li Yangyang Li Chen Chao Lucy Zhang Jian Peng Yanpeng Xing Yanpeng Xing Luyao Zhang Luyao Zhang Youjia Hu Zhiguang Zhou F. Susan Wong Li Wen IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice Frontiers in Immunology type 1 diabetes interleukin-10 neutrophils gut microbiota CD4+ T cells |
| title | IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice |
| title_full | IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice |
| title_fullStr | IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice |
| title_full_unstemmed | IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice |
| title_short | IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice |
| title_sort | il 10 deficiency accelerates type 1 diabetes development via modulation of innate and adaptive immune cells and gut microbiota in bdc2 5 nod mice |
| topic | type 1 diabetes interleukin-10 neutrophils gut microbiota CD4+ T cells |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.702955/full |
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