摘要
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.
基金
This work was supported by the National Institutes of Health(DK 045735,HD 097808,Diabetes Action Research and Education Foundation to L.W.)
the Diabetes Research Connection(to Y.H.and L.W.),a JDRF Postdoctoral Research Fellowship(3-PDF-2016-197-A-N,2016-2019)and a Medical Research Council Career Development Award(MR/T010525/1 to J.A.P.)
This work was supported by funding support from the National Institutes of Health(NIH),Juvenile Diabetes Research Foundation(JDRF),and Medical Research Council(MRC).
