Open AccessRegulation of B lymphocyte responses to T oll‐like receptor ligand binding during diabetes prevention in non‐obese diabetic ( NOD ) mice
Author(s) -
Wilson Christopher S.,
Elizer Sydney K.,
Marshall Andrew F.,
Stocks Blair T.,
Moore Daniel J.
Publication year - 2016
Publication title -
journal of diabetes
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.949
H-Index - 43
eISSN - 1753-0407
pISSN - 1753-0393
DOI - 10.1111/1753-0407.12263
Subject(s) - trif , nod mice , nod , immunology , t cell , receptor , microbiology and biotechnology , adoptive cell transfer , tlr3 , immune system , medicine , biology , toll like receptor , endocrinology , diabetes mellitus , innate immune system , autoimmunity
Background Interactions between genetic risk factors and the environment drive type 1 diabetes ( T1D ). The system of T oll‐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 (myeloid differentiation primary response 88 [ MyD88 ] vs TIR ‐domain‐containing adapter‐inducing interferon‐β [ TRIF ]) on B cell subsets via flow cytometry, including their activation, survival, proliferation, and cytoskeletal mobilization. The effect of polyinosinic‐polycytidylic acid (poly( I : C )) on diabetes development was addressed, including the B cell‐dependent activation of diabetes‐protective DX5 + cells, using genetic models and adoptive transfer. Results B lymphocytes from non‐obese diabetic ( NOD ) mice expressed enhanced levels of TLR ‐responsive proteins. Ex vivo analysis of B lymphocyte subsets demonstrated that TLR3 stimulation via TRIF deletes cells exhibiting a marginal zone phenotype, whereas MyD88 ‐dependent ligands enhance their survival. In vivo, marginal zone B cells were activated by poly( I : C ) and were unexpectedly retained in the spleen of NOD mice, in contrast with 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.