title: 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 (T1D). 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 (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.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Wilson
authors.affiliation: Department of Pediatrics, Ian Burr Division of Endocrinology and Diabetes, School of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Sydney K
authors.initials: SK
authors.lastname: Elizer
authors.affiliation: Department of Pediatrics, Ian Burr Division of Endocrinology and Diabetes, School of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Marshall
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, USA.|Vanderbilt Medical Scientist Training Program, Nashville, Tennessee, USA.
authors.forename: Blair T
authors.initials: BT
authors.lastname: Stocks
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, USA.|Department of Pediatrics, Ian Burr Division of Endocrinology and Diabetes, School of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Moore
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000276:immunology*; D003920:Diabetes Mellitus / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011070:Poly I-C / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051196:Toll-Like Receptor 3 / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000998:Antiviral Agents; D011070:Poly I-C; D051196:Toll-Like Receptor 3; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse
keywords: 1型糖尿病; B lymphocyte; B淋巴细胞; Toll-like receptor; Toll样受体; autoimmunity; innate immunity; type 1 diabetes; 先天性免疫; 自身免疫