Tr1 cells, but not Foxp3+ regulatory T cells, suppress NLRP3 inflammasome activation via an IL-10–dependent mechanism

Y Yao, J Vent-Schmidt, MD McGeough… - The Journal of …, 2015 - journals.aai.org
Y Yao, J Vent-Schmidt, MD McGeough, M Wong, HM Hoffman, TS Steiner, MK Levings
The Journal of Immunology, 2015journals.aai.org
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 …
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.
journals.aai.org