title: Tr1 Cells, but Not Foxp3+ Regulatory T Cells, Suppress NLRP3 Inflammasome Activation via an IL-10-Dependent Mechanism.
abstract: The two best-characterized types of CD4(+) regulatory T cells (Tregs) are Foxp3(+) Tregs and Foxp3(-) type 1 regulatory (Tr1) cells. The ability of Foxp3(+) Tregs and Tr1 cells to suppress adaptive immune responses is well known, but how these cells regulate innate immunity is less defined. We discovered that CD44(hi)Foxp3(-) T cells from unmanipulated mice are enriched in Tr1 cell precursors, enabling differentiation of cells that express IL-10, as well as Tr1-associated cell surface markers, CD49b and LAG-3, and transcription factors, cMaf, Blimp-1, and AhR. We compared the ability of Tr1 cells versus Foxp3(+) Tregs to suppress IL-1β production from macrophages following LPS and ATP stimulation. Surprisingly, Tr1 cells, but not Foxp3(+) Tregs, inhibited the transcription of pro-IL-1β mRNA, inflammasome-mediated activation of caspase-1, and secretion of mature IL-1β. Consistent with the role for IL-10 in Tr1 cell-mediated suppression, inhibition of inflammasome activation and IL-1β secretion was abrogated in IL-10R-deficient macrophages. Moreover, IL-1β production from macrophages derived from Nlrp3(A350V) knockin mice, which carry a mutation found in cryopyrin-associated periodic syndrome patients, was suppressed by Tr1 cells but not Foxp3(+) Tregs. Using an adoptive transfer model, we found a direct correlation between Tr1 cell engraftment and protection from weight loss in mice expressing a gain-of-function NLRP3. Collectively, these data provide the first evidence for a differential role of Tr1 cells and Foxp3(+) Tregs in regulating innate immune responses. Through their capacity to produce high amounts of IL-10, Tr1 cells may have unique therapeutic effects in disease-associated inflammasome activation.
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada V5Z 1M9; Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada V6X 3Z6; Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada V5Z 1M9; Child and Family Research Institute, Vancouver, British Columbia, Canada V5Z 4H4;
authors.forename: Yu
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada V5Z 1M9; Child and Family Research Institute, Vancouver, British Columbia, Canada V5Z 4H4;
authors.forename: Jens
authors.initials: J
authors.lastname: Vent-Schmidt
authors.affiliation: Department of Pediatrics, University of California, San Diego, San Diego, CA 92161;
authors.forename: Matthew D
authors.initials: MD
authors.lastname: McGeough
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada V5Z 1M9; Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada V6X 3Z6;
authors.forename: May
authors.initials: M
authors.lastname: Wong
authors.affiliation: Department of Pediatrics, University of California, San Diego, San Diego, CA 92161; Rady Children's Hospital, University of California, San Diego, San Diego, CA 92093.
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada V5Z 1M9; Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada V6X 3Z6;
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Steiner
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada V5Z 1M9; Child and Family Research Institute, Vancouver, British Columbia, Canada V5Z 4H4; mlevings@mail.ubc.ca.
authors.forename: Megan K
authors.initials: MK
authors.lastname: Levings
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation; D018920:Coculture Techniques; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D058847:Inflammasomes / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D039421:Integrin alpha2 / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics / Q000276:immunology; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D002352:Carrier Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556062:IL10 protein, mouse; D058847:Inflammasomes; D039421:Integrin alpha2; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C495608:Maf protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C513258:Prdm1 protein, mouse; D051257:Proto-Oncogene Proteins c-maf; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D016753:Interleukin-10; D000255:Adenosine Triphosphate; D000074462:Positive Regulatory Domain I-Binding Factor 1; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse