Tr1 Cells, but Not Foxp3+ Regulatory T Cells, Suppress NLRP3 Inflammasome Activation via an IL-10-Dependent Mechanism

J Immunol. 2015 Jul 15;195(2):488-97. doi: 10.4049/jimmunol.1403225. Epub 2015 Jun 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / pharmacology
  • Adoptive Transfer
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / immunology
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology
  • Cell Differentiation
  • Coculture Techniques
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology*
  • Gene Expression Regulation
  • Inflammasomes / drug effects
  • Inflammasomes / genetics
  • Inflammasomes / immunology*
  • Integrin alpha2 / genetics
  • Integrin alpha2 / immunology
  • Interleukin-10 / genetics
  • Interleukin-10 / immunology*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology
  • Lipopolysaccharides / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Positive Regulatory Domain I-Binding Factor 1
  • Proto-Oncogene Proteins c-maf / genetics
  • Proto-Oncogene Proteins c-maf / immunology
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / immunology
  • Signal Transduction
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / transplantation
  • Transcription Factors / genetics
  • Transcription Factors / immunology

Substances

  • Antigens, CD
  • CD223 antigen
  • Carrier Proteins
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • IL10 protein, mouse
  • Inflammasomes
  • Integrin alpha2
  • Interleukin-1beta
  • Lipopolysaccharides
  • Maf protein, mouse
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Prdm1 protein, mouse
  • Proto-Oncogene Proteins c-maf
  • Receptors, Aryl Hydrocarbon
  • Transcription Factors
  • Interleukin-10
  • Adenosine Triphosphate
  • Positive Regulatory Domain I-Binding Factor 1