Regulation of B lymphocyte responses to Toll‐like receptor ligand binding during diabetes prevention in non‐obese diabetic (NOD) mice

Abstract

Background Interactions between genetic risk factors and the environment drive Type 1 diabetes. The system of Toll-like receptors (TLR) detects these environmental triggers; however, the target cell that intermediates these interactions to drive T1D remains unknown. Methods We investigated the effect of TLR pathway activation (MyD88 vs TRIF) on B cell subsets via flow cytometry including their activation, survival, proliferation and cytoskeletal mobilization. The effect of polyIC on diabetes development was addressed including the B cell dependent activation of diabetes-protective DX5+ cells using genetic models and adoptive transfer. Results NOD B lymphocytes expressed enhanced levels of TLR responsive proteins. Ex vivo analysis of B lymphocyte subsets demonstrated that TLR3 stimulation via TRIF deletes cells displaying a marginal zone phenotype, whereas MyD88 dependent ligands enhance their survival. In vivo, marginal zone B cells were activated by polyIC and were unexpectedly retained in the spleen of NOD mice in contrast to the mobilization of these cells in non-autoimmune mice, a phenotype we traced to defective actin cytoskeletal dynamics. These activated B cells mediated TLR3-induced diabetes protection. Conclusions Immunotherapies must account for both B cell location and activation and these properties may differ in autoimmune and healthy settings. The significant finding of the study is that B lymphocytes respond to TLR ligation in a subset specific manner and are required for TLR-triggered diabetes protection. This study adds new information about the role of TLR ligation in diabetes pathogenesis and further identifies a unique role for B lymphocyte specific trafficking abnormalities in T1D.

Innate Viral Receptor Signaling Determines Type 1 Diabetes Onset

“…Unlike all other TLRs, TLR3 is MYD88-independent and instead utilizes the adaptor molecule TRIF for signal transduction following activation ( 44 ). The dsRNA mimetic polyinosinic:polycytidylic (poly I:C) is recognized by TLR3 and has been shown in various mouse studies to either protect or induce and increase severity of T1D depending on dose and administration ( 48 – 50 ). NOD mice deficient for TLR3 have high mortality from CVB4 infections and the few that survive develop T1D ( 51 ).…”

“…However, in some instances, TLR3-KO NOD mice can show less severe insulitis as well as some reduced susceptibility to T1D induction following CVB4 infection, but experience no difference in spontaneous disease development ( 52 ). TLR3 signaling within resident macrophages is critical for antiviral host defense to CVB4 as well as altering marginal zone B cell composition in NOD mice ( 50 , 51 ). This indicates that enhanced TLR3 activation may participate in T1D development as a result of virus infection.…”

Haploinsufficiency of the Myc regulator Mtbp extends survival and delays tumor development in aging mice

“…For analysis of healthy aged mice (29 months-old), the mice were starved for 5 hours and crown-to-rump length was measured. Blood was collected and analyzed for blood glucose levels with Accu-chek test strips (Roche Diagnostics, Indianapolis, IN, USA; [41], centrifuged and plasma frozen for later analysis. Mice were sacrificed by cervical dislocation.…”

Two to Tango: Dialogue between Adaptive and Innate Immunity in Type 1 Diabetes

“…More importantly, BTK mutation in the particular patient does not lead to complete loss of Β -cells [ 55 , 56 ]. In addition, active B-cells from NOD mice express increased levels of TLR-responsive proteins, which mediate TLR3-induced diabetes protection [ 57 ]. Furthermore, clinical trials have identified B-cells as possible therapeutic target for the prevention and reversal of T1DM [ 58 ].…”