title: TLR2 signaling improves immunoregulation to prevent type 1 diabetes.
abstract: Signaling through TLR2 promotes inflammation and modulates CD4(+) CD25(+) Tregs. We assessed mechanistically how this molecule would alter immunoregulation in type 1 diabetes (T1D). We also asked whether TLR2 may be involved in our recent discovery that viral infection can protect from autoimmune diabetes by expanding and invigorating Tregs. Treatment of prediabetic mice with a synthetic TLR2 agonist diminished T1D and increased the number and function of CD4(+) CD25(+) Tregs, also conferring DCs with tolerogenic properties. TLR2 ligation also promoted the expansion of Tregs upon culture with DCs and ameliorated their capacity to prevent the disease. Protection from T1D by lymphocytic choriomeningitis virus (LCMV) infection depended on TLR2. LCMV increased the frequency of CD4(+) CD25(+) Tregs and their production of TGF-β more significantly in WT than TLR2-deficient mice. Furthermore, LCMV infection in vivo or LCMV-infected DCs in vitro rendered, via TLR2, CD4(+) CD25(+) Tregs capable of diminishing T1D. We identify novel mechanisms by which TLR2 promotes immunoregulation and controls autoimmune diabetes in naïve or infected hosts. This work should help understand T1D etiology and develop novel immune-based therapeutic interventions.
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. cfilippi@gnf.org
authors.forename: Christophe M
authors.initials: CM
authors.lastname: Filippi
authors.forename: Katrin
authors.initials: K
authors.lastname: Ehrhardt
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Estes
authors.forename: Par
authors.initials: P
authors.lastname: Larsson
authors.forename: Janine E
authors.initials: JE
authors.lastname: Oldham
authors.forename: Matthias G
authors.initials: MG
authors.lastname: von Herrath
mesh_terms: D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D005434:Flow Cytometry; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D011236:Prediabetic State / Q000276:immunology; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D015704:CD4 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D016212:Transforming Growth Factor beta