Toll-like receptor 7 de fi ciency suppresses type 1 diabetes development by modulating B-cell differentiation and function

Innate immunity mediated by Toll-like receptors (TLRs), which can recognize pathogen molecular patterns, plays a critical role in type 1 diabetes development. TLR7 is a pattern recognition receptor that senses single-stranded RNAs from viruses and host tissue cells; however, its role in type 1 diabetes development remains unclear. In our study, we discovered that Tlr7 -de fi cient ( Tlr7 − / − ) nonobese diabetic (NOD) mice, a model of human type 1 diabetes, exhibited a signi fi cantly delayed onset and reduced incidence of type 1 diabetes compared with Tlr7 -suf fi cient ( Tlr7 + / + ) NOD mice. Mechanistic investigations showed that Tlr7 de fi ciency signi fi cantly altered B-cell differentiation and immunoglobulin production. Moreover, Tlr7 − / − NOD B cells were found to suppress diabetogenic CD4 + T-cell responses and protect immunode fi cient NOD mice from developing diabetes induced by diabetogenic T cells. In addition, we found that Tlr7 de fi ciency suppressed the antigen-presenting functions of B cells and inhibited cytotoxic CD8 + T-cell activation by downregulating the expression of both nonclassical and classical MHC class I (MHC-I) molecules on B cells. Our data suggest that TLR7 contributes to type 1 diabetes development by regulating B-cell functions and subsequent interactions with T cells. Therefore, therapeutically targeting TLR7 may prove bene fi cial for disease protection.

[1]  L. Wen,et al.  Norovirus Changes Susceptibility to Type 1 Diabetes by Altering Intestinal Microbiota and Immune Cell Functions , 2019, Front. Immunol..

[2]  T. Abe,et al.  Identification of U11snRNA as an endogenous agonist of TLR7-mediated immune pathogenesis , 2019, Proceedings of the National Academy of Sciences.

[3]  Yasser B. Ruiz-Blanco,et al.  Control of TLR7-mediated type I IFN signaling in pDCs through CXCR4 engagement—A new target for lupus treatment , 2019, Science Advances.

[4]  G. Gibson,et al.  Distinct Effector B Cells Induced by Unregulated Toll‐like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus , 2018, Immunity.

[5]  E. Bonifacio,et al.  Immunological biomarkers for the development and progression of type 1 diabetes , 2018, Diabetologia.

[6]  Hongyu Zhao,et al.  Toll-like receptor 9 negatively regulates pancreatic islet beta cell growth and function in a mouse model of type 1 diabetes , 2018, Diabetologia.

[7]  Toshiyuki Shimizu,et al.  Structural Analysis Reveals that Toll-like Receptor 7 Is a Dual Receptor for Guanosine and Single-Stranded RNA. , 2016, Immunity.

[8]  N. Morgan,et al.  Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes , 2016, Diabetologia.

[9]  L. Wen,et al.  Altered Peripheral B-Lymphocyte Subsets in Type 1 Diabetes and Latent Autoimmune Diabetes in Adults , 2015, Diabetes Care.

[10]  P. Volchkov,et al.  Microbiota regulates type 1 diabetes through Toll-like receptors , 2015, Proceedings of the National Academy of Sciences.

[11]  Sky W. Brubaker,et al.  Innate immune pattern recognition: a cell biological perspective. , 2015, Annual review of immunology.

[12]  Toshiyuki Shimizu,et al.  Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases , 2015, Nature Communications.

[13]  B. Coulson,et al.  Rotavirus Activates Lymphocytes from Non-Obese Diabetic Mice by Triggering Toll-Like Receptor 7 Signaling and Interferon Production in Plasmacytoid Dendritic Cells , 2014, PLoS pathogens.

[14]  H. Kolb,et al.  Toll-Like Receptor 4 Deficiency Accelerates the Development of Insulin-Deficient Diabetes in Non-Obese Diabetic Mice , 2013, PloS one.

[15]  L. Wen,et al.  TLR9 Deficiency Promotes CD73 Expression in T Cells and Diabetes Protection in Nonobese Diabetic Mice , 2013, The Journal of Immunology.

[16]  M. Atkinson,et al.  Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients , 2012, The Journal of experimental medicine.

[17]  J. Dutz,et al.  Toll-like receptor 7 stimulation promotes autoimmune diabetes in the NOD mouse , 2011, Diabetologia.

[18]  A. Cooke,et al.  Immune cell crosstalk in type 1 diabetes , 2010, Nature Reviews Immunology.

[19]  S. Akira,et al.  The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors , 2010, Nature Immunology.

[20]  I. Shimomura,et al.  Expression of toll-like receptors in the pancreas of recent-onset fulminant type 1 diabetes. , 2010, Endocrine journal.

[21]  Jeffrey A. Bluestone,et al.  Genetics, pathogenesis and clinical interventions in type 1 diabetes , 2010, Nature.

[22]  J. Shupe,et al.  TLR9 Regulates TLR7- and MyD88-Dependent Autoantibody Production and Disease in a Murine Model of Lupus , 2010, The Journal of Immunology.

[23]  S. Richardson,et al.  Analysis of islet inflammation in human type 1 diabetes , 2009, Clinical and experimental immunology.

[24]  G. Ciliberto,et al.  The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells , 2009, The Journal of experimental medicine.

[25]  M. Fischer,et al.  Toll‐like Receptors in Autoimmunity , 2008, Annals of the New York Academy of Sciences.

[26]  Kun Wook Chung,et al.  Toll-like receptor 2 senses beta-cell death and contributes to the initiation of autoimmune diabetes. , 2007, Immunity.

[27]  J. Shupe,et al.  Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. , 2006, Immunity.

[28]  Akiko Iwasaki,et al.  Recognition of single-stranded RNA viruses by Toll-like receptor 7. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[29]  R. Slattery,et al.  Beta cell MHC class I is a late requirement for diabetes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[30]  S. Akira,et al.  Toll-like receptors: critical proteins linking innate and acquired immunity , 2001, Nature Immunology.

[31]  C. Janeway,et al.  Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library , 1999, Nature Medicine.

[32]  T. Honjo,et al.  Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. , 1999, Immunity.

[33]  R. Tisch,et al.  B lymphocytes are critical antigen-presenting cells for the initiation of T cell-mediated autoimmune diabetes in nonobese diabetic mice. , 1998, Journal of immunology.

[34]  C. Janeway,et al.  The Role of Lymphocyte Subsets in Accelerated Diabetes in Nonobese Diabetic–Rat Insulin Promoter–B7-1 (NOD-RIP-B7-1) Mice , 1998, The Journal of experimental medicine.

[35]  S. Wakana,et al.  Direct evidence for the contribution of B cells to the progression of insulitis and the development of diabetes in non-obese diabetic mice. , 1997, International immunology.

[36]  M. Zeleňáková,et al.  B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new "speed congenic" stock of NOD.Ig mu null mice , 1996, The Journal of experimental medicine.

[37]  C. Janeway,et al.  CD8 T cell clones from young nonobese diabetic (NOD) islets can transfer rapid onset of diabetes in NOD mice in the absence of CD4 cells , 1996, The Journal of experimental medicine.

[38]  K. Yamagata,et al.  Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients. , 1993, The Journal of clinical investigation.

[39]  C. Benoist,et al.  Following a diabetogenic T cell from genesis through pathogenesis , 1993, Cell.

[40]  M. McGill,et al.  Insulitis in type 1 (insulin‐dependent) diabetes mellitus in man—macrophages, lymphocytes, and interferon‐γ containing cells , 1991, The Journal of pathology.

[41]  R. Flavell,et al.  Duplicated gene pairs and alleles of class I genes in the Qa2 region of the murine major histocompatibility complex: a comparison. , 1985, The EMBO journal.

[42]  M. Madaio,et al.  Interferon-α accelerates murine systemic lupus erythematosus in a T cell-dependent manner. , 2011, Arthritis and rheumatism.

[43]  P. Santamaria,et al.  CD8+ T cells in type 1 diabetes. , 2008, Advances in immunology.

[44]  J. Harley,et al.  High serum IFN-alpha activity is a heritable risk factor for systemic lupus erythematosus. , 2007, Genes and immunity.

[45]  J. Banchereau,et al.  IFN-alpha induces early lethal lupus in preautoimmune (New Zealand Black x New Zealand White) F1 but not in BALB/c mice. , 2005, Journal of immunology.

[46]  Andreas Dengel,et al.  A comparison on neural net simulators , 1993, IEEE Expert.