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 CD44hiFoxp3− 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 Nlrp3A350V 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.

NKG2C/E Marks the Unique Cytotoxic CD4 T Cell Subset, ThCTL, Generated by Influenza Infection

“…FoxP3 + Tregs can also be cytotoxic (55), however ThCTL are FoxP3 negative. Type 1 regulatory cells lack FoxP3 expression as well, however these cells often express high levels of Lag-3 (56, 57), which ThCTL are low for at the peak of the infection. The lack of transcription factors associated with the other major CD4 subsets, suggests that few if any of the ThCTL have differentiated down other polarized cytokine pathways including those expressed by Th2 (GATA-3 expressing), T FH (Bcl6-expressing), Th17 (RORγt) or FoxP3 + Treg.…”

Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn’s disease

“…This is shown in studies of mice with abnormalities of IL-10 production or signaling, where IL-10 has been shown to have a profound inhibitory effect on NLRP3 inflammasome activity; therefore, the absence of IL-10 leads to increased IL-1β production (27). In these studies, it has been shown that IL-10-KO and IL-10R-KO mice exhibit increased NLRP3 inflammasome activity and that an NLRP3 inflammasome inhibitor, such as glyburide or caspase-1 inhibitor, ameliorates colitis occurring in such mice (28,29).…”

Blurring the Lines Between Innate and Adaptive Immunity

“…Inflammasome activation is required for protective immune responses against certain pathogens and participates in a wide array of disease processes, including ischemia reperfusion injury with relevance to transplantation. Previously published work has additionally shown that complement activation and insertion of the MAC into myeloid cells triggers inflammasome activation, delineating an interactive crosstalk mechanism between these 2 innate immune systems 8 .…”