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Origin: Periphery
Markers: CD4+, CD25 high, FoxP3 high, CD45RA-, CD45RO+, CD127 low HLA-DR -, CD95+, CTLA4+, Ki67+, ICOS+/-
Key features: Regulatory T Cells (Tregs) suppress T cell responses
CD4+ CD25++ FOXP3 low nTreg / tTreg are transformed extrathymically at peripheral sites to CD4+ CD25+ FOXP3 high Treg (peripherally induced) by TGF-beta from APCs
However, CD4+ CD25+ FOXP3 high Treg (peripherally induced) are generated from Naive CD4+ T Cells rather than in the thymus. Unlike CD4+ CD25++ FOXP3 low nTreg / tTregs, they respond to non-self-antigens, which are usually derived from food and microbes. Most of these CD4+ CD25+ FOXP3 high Treg (peripherally induced) are trained and remain in the intestine (Intestinal CD4+ CD25+ FOXP3 high Treg (peripherally induced)), where they play a crucial role in maintaining tissue homeostasis.
CD4+ CD25+ FOXP3 high Treg (peripherally induced) are a subset of CD4+ CD25+ Treg that develop outside the thymus, in peripheral tissue. These cells are distinct from CD4+ CD25++ FOXP3 low nTreg / tTreg.
Peripheral Tregs develop when Naive CD4+ T Cells are activated in the presence of Transforming growth factor beta (TGF-beta) and interleukin-2 into the absence of interleukin-6 and other pro-inflammatory cytokines. Another factor that is critical to Peripheral Tregs cell development is Retinoic Acid (RA) (all-trans-retinoic acid) that binds RAR-related orphan receptor (ROR)
Colonization of germ-free mice with commensals, especially RAR-related Orphan Receptor Gamma/T (ROR-gamma/t) Isoform 2 (NR1F3)t+ Foxp3+ Colonic Treg cells inducers, broadly diminished colon neuronal density
CD4+ CD25+ FOXP3 high Treg (peripherally induced), unlike CD4+ CD25++ FOXP3 low nTreg / tTreg, can potentially revert to conventional CD4+ T cells.
Regulatory T Cells (Tregs) exert their suppressive functions by secreting Interleukin-10 (IL-10), Transforming growth factor beta (TGF-beta) and upregulating several inhibitory molecules.
CD4+ CD25+ Treg are potent suppressors of immune responses and crucial for the prevention of autoimmune diseases
Sakaguchi et al. 2008
Regulatory T Cells (Tregs) cells are crucial for immune balance but hinder anti-cancer immunity by thriving in the tumor microenvironment (TME), which is metabolically challenging for effector T cells
Homeostatic roles have been attributed to distinct populations of CD4+ CD25+ FOXP3 high Treg (peripherally induced) operating in a variety of tissues, including:
Natural CD4+ CD25+ Treg constitute <5% of peripheral CD4+ T cells in humans
In the colon and small intestine, CD4+ CD25+ FOXP3 high Treg (peripherally induced) exhibit distinct phenotypic and likely functional characteristics. In the small intestine, Tregs are induced as a response to food antigens, whereas in the colon, they are induced in response to gut bacteria. When comparing conventionally-housed mice to germ-free mice, it was observed that the Tregs in the colon of germ-free mice were significantly reduced. However, the Tregs in the small intestine remained relatively unaffected under germ-free conditions.
Less functional reliance on PI3K Signal transduction pathway and MAPK / ERK Pathway in Tregs compared with conventional CD4+ and CD8+ lymphocytes
Extrathymic differentiation of Treg cells impacts commensal microbiota composition and serves a distinct, essential function in restraint of allergic type inflammation at mucosal interfaces
In mice, RAR-related Orphan Receptor Gamma/T (ROR-gamma/t) Isoform 2 (NR1F3)t+ Foxp3+ Colonic Treg cells were most abundant in the colonic Mucosa / Mucous membrane. Regulatory T Cells (Tregs) have a central role in the suppression of inflammatory and allergic responses
CD4+ CD25+ FOXP3 high Treg (peripherally induced)) can suppress the activation, proliferation and effector functions - such as cytokine production - of a wide range of immune cells, including CD4+ and CD8+ T cells, natural killer (NK) and NKT cells, B cells / B Lymphocytes and antigen-presenting cells (APCs) in vitro and in vivo. CD4+ CD25+ FOXP3 high Treg (peripherally induced) can also suppress antitumor immune responses and favor tumor progression
The conversion of peripheral Naive CD4+ T cells to CD4+ CD25+ FOXP3 high Treg (peripherally induced) by Transforming growth factor beta (TGF-beta) induction of transcription factor Foxp3 / FOXP3 / Scurfin
In addition, by not requiring specific antigen recognition, these Tregs can modulate immune responses against a wide range of antigens and in various contexts
Some Regulatory T Cells (Tregs) can produce Interleukin-17 Family / Interleukin-17 (IL-17)
Only ~1–2% of cells with the highest CD25 (CD4+ CD25+) expression have been shown to be functionally suppressive and can be considered CD4+ CD25+ Treg (peripherally induced)
CD4+ CD25+ Treg express the biomarkers CD4, FOXP3, and CD25 / IL2RA and are thought to be derived from the same lineage as naïve CD4+ cells
Natural Killer T cells (NKT cells) are not strictly considered a subtype of regulatory T cells, but they do share some regulatory functions.
see also:
CD4+ CD25+ FOXP3 high Treg (peripherally induced) & Inflammation / Inflammatory Diseases
Intestinal CD4+ CD25+ FOXP3 high Treg (peripherally induced)
RAR-related Orphan Receptor Gamma/T (ROR-gamma/t) Isoform 2 (NR1F3)t + Foxp3 + Colonic Treg cells