• Yu Yao, Jens Vent-Schmidt, Matthew D McGeough, May Wong, Hal M Hoffman, Theodore S Steiner, and Megan K Levings.
• 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;
• J. Immunol. 2015 Jul 15; 195 (2): 488-97.

AbstractThe 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.

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