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.
Copyright © 2015 by The American Association of Immunologists, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / pharmacology
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Adoptive Transfer
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Animals
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Antigens, CD / genetics
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Antigens, CD / immunology
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Bone Marrow Cells / cytology
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / immunology
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Carrier Proteins / genetics
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Carrier Proteins / immunology
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Cell Differentiation
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Coculture Techniques
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / immunology*
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Gene Expression Regulation
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Inflammasomes / drug effects
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Inflammasomes / genetics
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Inflammasomes / immunology*
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Integrin alpha2 / genetics
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Integrin alpha2 / immunology
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Interleukin-10 / genetics
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Interleukin-10 / immunology*
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Interleukin-1beta / genetics
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Interleukin-1beta / immunology
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Lipopolysaccharides / pharmacology
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Lymphocyte Activation Gene 3 Protein
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Transgenic
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NLR Family, Pyrin Domain-Containing 3 Protein
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Positive Regulatory Domain I-Binding Factor 1
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Proto-Oncogene Proteins c-maf / genetics
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Proto-Oncogene Proteins c-maf / immunology
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Receptors, Aryl Hydrocarbon / genetics
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Receptors, Aryl Hydrocarbon / immunology
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Signal Transduction
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T-Lymphocytes, Regulatory / cytology
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / transplantation
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Transcription Factors / genetics
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Transcription Factors / immunology
Substances
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Antigens, CD
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Carrier Proteins
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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IL10 protein, mouse
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Inflammasomes
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Integrin alpha2
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Interleukin-1beta
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Lipopolysaccharides
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Maf protein, mouse
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Prdm1 protein, mouse
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Proto-Oncogene Proteins c-maf
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Receptors, Aryl Hydrocarbon
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Transcription Factors
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Interleukin-10
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Adenosine Triphosphate
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Positive Regulatory Domain I-Binding Factor 1
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Lymphocyte Activation Gene 3 Protein
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Lag3 protein, mouse