title: Toso controls encephalitogenic immune responses by dendritic cells and regulatory T cells.
abstract: The ability to mount a strong immune response against pathogens is crucial for mammalian survival. However, excessive and uncontrolled immune reactions can lead to autoimmunity. Unraveling how the reactive versus tolerogenic state is controlled might point toward novel therapeutic strategies to treat autoimmune diseases. The surface receptor Toso/Faim3 has been linked to apoptosis, IgM binding, and innate immune responses. In this study, we used Toso-deficient mice to investigate the importance of Toso in tolerance and autoimmunity. We found that Toso(-/-) mice do not develop severe experimental autoimmune encephalomyelitis (EAE), a mouse model for the human disease multiple sclerosis. Toso(-/-) dendritic cells were less sensitive to Toll-like receptor stimulation and induced significantly lower levels of disease-associated inflammatory T-cell responses. Consistent with this observation, the transfer of Toso(-/-) dendritic cells did not induce autoimmune diabetes, indicating their tolerogenic potential. In Toso(-/-) mice subjected to EAE induction, we found increased numbers of regulatory T cells and decreased encephalitogenic cellular infiltrates in the brain. Finally, inhibition of Toso activity in vivo at either an early or late stage of EAE induction prevented further disease progression. Taken together, our data identify Toso as a unique regulator of inflammatory autoimmune responses and an attractive target for therapeutic intervention.
authors.affiliation: The Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1.
authors.forename: Dirk
authors.initials: D
authors.lastname: Brenner
authors.forename: Anne
authors.initials: A
authors.lastname: Brüstle
authors.forename: Gloria H Y
authors.initials: GH
authors.lastname: Lin
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Duncan
authors.forename: Christiane B
authors.initials: CB
authors.lastname: Knobbe-Thomsen
authors.forename: Michael
authors.initials: M
authors.lastname: St Paul
authors.forename: Colin
authors.initials: C
authors.lastname: Reardon
authors.forename: Michael W
authors.initials: MW
authors.lastname: Tusche
authors.forename: Bryan
authors.initials: B
authors.lastname: Snow
authors.forename: Sara R
authors.initials: SR
authors.lastname: Hamilton
authors.forename: Aline
authors.initials: A
authors.lastname: Pfefferle
authors.forename: Syed O
authors.initials: SO
authors.lastname: Gilani
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: Karl S
authors.initials: KS
authors.lastname: Lang
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000628:therapy; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology; D058504:Th17 Cells / Q000166:cytology; D013997:Time Factors
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; C499656:Fcmr protein, mouse; D008565:Membrane Proteins
keywords: Th1/Th17 cells; inflammation