Thymus-derived Foxp3+ regulatory T cells upregulate RORγt expression under inflammatory conditions

IL‐33‐activated murine mast cells control the dichotomy between RORγt+ and Helios+Tregs via the MK2/3‐mediated IL‐6 production in vitro

“…RORγt + T regs have been proven to represent a stable, distinct T reg subpopulation . Upon stimulation with IL‐6 in vitro, they can be generated from thymic T regs , but not from naïve Th cells, and have been shown to be very effective in the protection from T cell‐mediated colitis . In vivo, the formation of RORγt + T regs in the gastrointestinal tract depends on the presence of microbiota and IL‐6 .…”

“…However, while the development of Helios + T regs is independent from microbiota, RORγt + T regs are virtually absent in germ‐free mice . Despite RORγt + T regs can be generated from thymic T regs via IL‐6R stimulation, the cellular source IL‐6 has not been found, yet. Whereas IL‐33 is involved in the maintenance of ST2 + Helios + T regs , the role of IL‐33 for the generation of RORγt + T regs remains elusive.…”

Developmental and cellular age direct conversion of CD4+ T cells into RORγ+ or Helios+ colon Treg cells

“…IL6 is important for the generation or maintenance of RORγ + Treg cells, with a twofold reduction in its absence (Ohnmacht et al, 2015;Yissachar et al, 2017), an effect that can be reproduced in vitro (Kim et al, 2017;Yang et al, 2018). We compared the role of IL6 signals in Treg cell conversion from infant or adult naive T cells using Il6ra fl/fl xCd4Cre mice.…”

“…However, several lines of evidence later suggested more intricate relationships between Helios + and RORγ + Treg cells. First, RORγ could be induced in tTreg cells by TCRmediated activation in vitro in the presence of IL6 (Kim et al, 2017;Yang et al, 2018), which is of potential relevance because RORγ + Treg cells depend on IL6 in vivo (Ohnmacht et al, 2015;Yissachar et al, 2017). Second, using a transgenic mouse model expressing a TCR reactive to an antigen of microbial origin, Hsieh and colleagues showed that Tconv cells could be efficiently converted in vitro and in vivo by exposure to cognate microbial antigen, mostly to RORγ + Treg cells via a FoxP3 + RORγ − intermediate (Nutsch et al, 2016;Solomon and Hsieh, 2016), thus suggesting that colonic Treg cells of Helios + and RORγ + phenotypes might be interconnected.…”

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

“…These tTreg cells are complemented by peripherally induced Treg cells (pTreg cells), which convert from naive Foxp3 − CD4 + T cells preferentially at mucosal sites . A number of proteins like Helios, Neuropilin‐1 (Nrp‐1), or RAR‐related orphan receptor gamma (RORγt) were suggested to distinguish between tTreg and pTreg cells , yet their usability particularly under inflammatory conditions has been questioned . Importantly, accumulating evidence suggests that the Foxp3 + Treg cell population is not homogeneous and that co‐expression of additional transcription factors, such as T‐box transcription factor TBX21 (T‐bet), GATA binding protein 3 (Gata‐3), RORγt, or IFN regulatory factor 4 (Irf4), is required for the acquisition of unique functional properties within highly specialized Treg cell subsets .…”