RAR-related Orphan Receptor Gamma/T (ROR-gamma/t) Isoform 2 (NR1F3)t+ Foxp3+ Colonic Treg cells

Cell definition

A subgroup of RAR-related Orphan Receptor Gamma/T (ROR-gamma/t) Isoform 2 (NR1F3)t+ Foxp3+ Colonic Treg cells are PD-1− CXCR3+ Tregs with improved suppressive abilities, including through increased Interleukin-10 (IL-10) Production (1).

Secretion of Anti-inflammatory cytokines by RAR-related Orphan Receptor Gamma/T (ROR-gamma/t) Isoform 2 (NR1F3)t+ Foxp3+ Colonic Treg cells and macrophages further induces intestinal homeostasis or tolerance to inflammation (2).

Colonic RORg + Treg cells are a specialized microbiota-dependent population crucial for intestinal homeostasis (3).

Induction triggers

Both Transforming growth factor beta (TGF-beta) and Retinoic Acid (RA) (all-trans-retinoic acid) are abundant in the mucosa of the gut, where are the antigens derived from commensal microbes stimulate the development of peripheral Tregs to maintain tolerance to the gut microbiota (4)

RAR-related Orphan Receptor Gamma/T (ROR-gamma/t) Isoform 2 (NR1F3)t-expressing regulatory T cells (Tregs) are induced by microbes, which is essential for controlling intestinal inflammation (5).

A distinct Treg population expressing the transcriptional factor RORγ is induced in the colonic lamina propria by colonization with gut symbionts (6,7, 8, 9, 10, 11, 12).

Colonic RORg + Treg cells are mostly locally induced in response to microbial or food antigens (6, 7, 13, 14, 15)

Tissue identity

They belong to the so-called ‘‘tissue-Treg cells,’’ which are a specialized category of Treg cells with distinct transcriptomes and T cell receptor (TCR) repertoires that are located in non-lymphoid tissues - for example, visceral adipose tissue , skeletal muscle , skin , and the colonic lamina propria (16).

Unlike thymic Tregs , colonic RORγ + Tregs have a distinct phenotype (Helios – and Nrp1 –), and their accumulation is influenced by enteric factors derived from diet or commensal colonization (6, 7).

RAR-related orphan receptor gamma/t (ROR-gamma/t) (NR1F3) determines a specific signature and function in RAR-related Orphan Receptor Gamma/T (ROR-gamma/t) Isoform 2 (NR1F3)t+ Foxp3+ Colonic Treg cells (7).

RAR-related Orphan Receptor Gamma/T (ROR-gamma/t) Isoform 2 (NR1F3)t+ Foxp3+ Colonic Treg cells represent the central subgroup of Tregs in the colon and differentiate locally from 15–20 days of age in response to bacterial antigens (6, 7).

In mice, regulatory T cells (Tregs) were found to be most abundant in the Colon Mucus Layers / Colon Mucosa (17).

Suppressive role

The PD-1− CXCR3+ subset exhibits enhanced suppressive abilities through increased Interleukin-10 (IL-10) Production (1)

Secretion of anti-inflammatory cytokines by RORγt+ Foxp3+ colonic Treg cells and macrophages induces intestinal homeostasis and tolerance to inflammation (2).

These cells play an indispensable role in maintaining intestinal tolerance (6, 7, 18, 15).

Disease links

Food allergy patients have fewer RAR-related Orphan Receptor Gamma/T (ROR-gamma/t) Isoform 2 (NR1F3)t+ Foxp3+ Colonic Treg cells, and commensal bacteria-mediated protection against food allergy depends on these cells (15).

The function of colonic RORg +Treg cells has so far been linked primarily to mucosal health as they play an indispensable role in maintaining intestinal tolerance, with their loss resulting in increased incidences of colitis, colon cancer, and food allergies (6, 7, 11, 15, 19, 20).

Mice lacking RAR-related Orphan Receptor Gamma/T (ROR-gamma/t) Isoform 2 (NR1F3)t+ Foxp3+ Colonic Treg cells show microbial dysbiosis and an increase in inflammatory Th17 cells and are more susceptible to colitis in various models (6, 7, 11, 19, 20, 21).

Microbial reliance

A distinct Treg population expressing RAR-related orphan receptor gamma/t (ROR-gamma/t) Isoform 2 (NR1F3) is induced in the colonic lamina propria by colonization with gut symbionts (6, 7, 8, 9, 10, 11, 12).

RAR-related Orphan Receptor Gamma/T (ROR-gamma/t) Isoform 2 (NR1F3)t+ Foxp3+ Colonic Treg cells are mostly locally induced in response to microbial or food antigens, demonstrating their microbiota-dependent nature (6, 7, 13, 14, 15).

Mice lacking these cells show microbial dysbiosis, highlighting the bidirectional relationship between RAR-related Orphan Receptor Gamma/T (ROR-gamma/t) Isoform 2 (NR1F3)t+ Foxp3+ Colonic Treg cells and commensals (6, 7, 15, 18, 20, 21).

References

(1) Byun et al. 2024 J Immunol 213(6): 886–897
(2) Wangchuk et al. 2024 Trends in Pharmacological Sciences 45(10): 892-903
(3) Hanna et al. 2023 Immunity 56(4): 829-846
(4) Murphy et al. 2022 W.W. Norton & Company ISBN 978-0-393-68093-5
(5) Ramanan et al. 2020 Cell 181(6): 1276-1290
(6) Ohnmacht et al. 2015 Science 349: 989–993
(7) Sefik et al. 2015 Science 349(6251): 993-997
(8) Kim et al. 2016e Science 351: 858-863
(9) Geva-Zatorsky et al. 2017 Cell 168: 928-943
(10) Yissachar et al. 2017 Cell 168: 1135–1148
(11) Xu et al. 2018b Nature 554: 373–377
(12) Kuipers et al. 2020 Cell Metab. 31: 445–447
(13) Kim et al. 2016e Science 351: 858-863
(14) Yang et al. 2016 Mucosal Immunol. 9: 444–457
(15) Abdel-Gadiret al. 2019 Nat. Med. 25: 1164–1174
(16) Mun˜oz-Rojas & Mathis 2021 Nat. Rev. Immunol. 21: 597–611
(17) Atarashi et al. 2011
(18) Xu et al. 2018b Nature 554: 373–377
(19) Al Nabhani et al. 2019 Immunity 50: 1276–1288
(20) Neumann et al. 2019 Nat. Immunol. 20: 471–481
(21) Ye et al. 2017 Cell Rep. 21: 2277-2290

see also:
CD4+ CD25+ FOXP3 high Treg (peripherally induced)
Inflammation / Inflammatory diseases & Secondary bile salts / Secondary bile acids (SBAs)
RAR-related Orphan Receptor Gamma/T (ROR-gamma/t) Isoform 2 (NR1F3)t+ Foxp3+ Colonic Treg cells & Short-chain fatty acids (SCFAs)