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

Juan Huang,Luyao Zhang,Jian Peng,Jianlei Gu,Ningwen Tai,Youjia Hu,James Alexander Pearson,Li Wen,Zhiguang Zhou,Hongyu Zhao,F Susan Wong,Jianping Jiang,Georgios Efthimiou,Yanpeng Xing

doi:10.1038/s41423-020-00590-8

Abstract

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-deficient (Tlr7−/−) nonobese diabetic (NOD) mice, a model of human type 1 diabetes, exhibited a significantly delayed onset and reduced incidence of type 1 diabetes compared with Tlr7-sufficient (Tlr7+/+) NOD mice. Mechanistic investigations showed that Tlr7 deficiency significantly altered B-cell differentiation and immunoglobulin production. Moreover, Tlr7−/− NOD B cells were found to suppress diabetogenic CD4+ T-cell responses and protect immunodeficient NOD mice from developing diabetes induced by diabetogenic T cells. In addition, we found that Tlr7 deficiency 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 beneficial for disease protection.

Highlights

Type 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin‐producing pancreatic β‐cell mediated by autoreactive immune cells[1] that involves both innate and adaptive immunity.[2]
No significant difference in the incidence of diabetes development was observed between male Tlr7−/− nonobese diabetic (NOD) mice and male Tlr7+/+ NOD littermates, the overall incidence of T1D was much lower in male Tlr7−/− NOD mice than in male Tlr7+/+ NOD littermates (Fig. 1B)
When purified B cells from Tlr7−/− NOD mice had no contact with Tlr7−/− NOD CD4+ T cells, we found an increase in CD4+ T-cell proliferation (Fig. 5I), which was distinctly different from the suppression seen when CD4+ T cells were in direct contact with Tlr7−/− NOD B cells (Fig. 5E)

Summary

Introduction

Type 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin‐producing pancreatic β‐cell mediated by autoreactive immune cells[1] that involves both innate and adaptive immunity.[2]. TLRs can recognize microbe-derived lipids, lipoproteins, and proteins; several intracellular TLRs, including TLR3, TLR7, TLR8, and TLR9, sense bacterial and viral nucleic acids.[4,5] In addition to roles in immune responses to pathogens, TLRs can modulate the susceptibility to autoimmune diseases, such as systemic lupus erythematosus (SLE)[6,7] and arthritis.[8] In SLE-prone. TLR9 regulates TLR7-dependent autoantibody production and disease progression in MRL/lpr mice,[10] suggesting important crosstalk between these TLRs. In T1D studies, Tlr[2] or Tlr[9] deficiency in nonobese diabetic (NOD) mice led to protection from T1D development,[11,12,13,14] whereas Tlr[4] deficiency accelerated disease progression.[15,16] TLR7, another member of the TLR family, is mainly expressed in immune cells[4,5,17] and can recognize single-stranded

Methods

Results

Conclusion