Treg cells directly regulate the activity of the innate immune system through their interaction with mononuclear phagocytes, granulocytes, dendritic cells, and innate lymphocytes, influencing autoimmune or non-autoimmune inflammation. It mainly affects cell survival, proliferation, cytokine production, phagocytosis, cytotoxicity and modification of other effector functions.
Interaction with monocytes
Front. Immunol.
1. Treg can promote the phenotypic differentiation of monocytes into CD206+ M2-like macrophages, thereby directly regulating the inflammatory process of monocytes and has a potential role. Its characteristics are:
- increased phagocytic activity and expression of related marker proteins (CD206, CD163 and heme oxygenase-1);
- decreased antigen presentation capacity (CD40, CD80/86, and class II MHC expression);
- Increases the secretion of anti-inflammatory cytokines such as IL-10 and reduces the production of pro-inflammatory molecules such as TNF, IL-6, nitric oxide (NO), and reactive oxidizing species (ROS).
The effect of Treg on monocyte macrophage differentiation is as much related to cellular contact as it is to cytokines.
- IL-10, IL-13, TGF-β, IL-4, arginase and soluble fibrinogen-like protein 2 are involved.
- Transcription factor Krüppel-like factor10 (KLF10) and mammalian target rapamycin complex 1 (MTORC1)-mediated signaling pathway is also required for Treg to inhibit macrophage-mediated inflammation.
However, since the role of macrophages in inflammatory diseases is not strictly differentiated according to the M1/M2 phenotype, Treg-induced macrophage M2-like polarization may also exacerbate the fibrotic manifestations of the disease.
(2) Treg also expresses a variety of mediators of programmed cell death and may inhibit inflammation by inducing apoptosis in monocytic phagocytic cells.
Unlike Treg to kill CD4+ T cells through the TRAIL/TRAILR and Galectin signaling pathways, current hypotheses for the pathway by which Treg kills monocytes macrophages include inducing downregulation of the apoptosis marker CD14 in endotoxin-activated mononuclear phagocytic cells through Fas/FasL interactions, as is the case with effector T cells.
(3) Treg regulates the phagocytosis/decomposition ability of tissue-resident macrophages.
This ability is mediated primarily by the secretion of IL-10 by Treg and IL-13 by macrophages.
For example, in atherosclerosis, the phagocytosis of macrophages helps in the breakdown of plaque in the artery wall. Treg regulates phenotype (upregulates CD163, down-regulates RTIB) and cytokine production (down-regulates TNF, IL-1β, and IL-6) of resident macrophages (microglia) in an IL-10-dependent manner to maintain immune homeostasis in the central nervous system.
Interaction with granulocytes
Front. Immunol.
Neutrophils
Treg can mediate anti-inflammatory and pro-tolerance effects by affecting neutrophils.
Endotoxin or CD3/CD28 ligands activate Treg to promote apoptosis in neutrophils and also induce the expression of a range of immunosuppressive pathways through different mediators.
CD4+ CD25+ Treg has been shown to recruit neutrophils by secreting CXCL8 in vitro. Human neutrophils co-cultured with activated Treg secreted anti-inflammatory molecules such as IL-10, TGF-β1, IDO, and HO-1 are more active. Upregulation of IDO is dependent on CTLA-4 expression on Treg.
In a mouse model of sepsis, adoptive transfer of CD4+ CD25hi CD127low Tregs relied on ICAM-1 and CD11b to eliminate neutrophil overactivation, increase neutrophil apoptosis, and reduce mortality in p110δD910A mice after LPS challenge.
In turn, neutrophil extracellular traps (NETs) have been shown to promote the differentiation of primitive CD4+ T cells into Treg for inhibition in different animal model settings.
In the skin, integrin aVβ8+ Treg uses the potentially activated TGF-β in a cell-dependent manner to induce keratinocytes to express CXCL5 and recruit neutrophils, resulting in delayed epithelial regeneration.
Mast cells
Mast cells (MCs) are tissue-resident granulocytes that generally play a pro-inflammatory role in infections and allergic reactions. Treg cells regulate MC activation and migration through multiple mechanisms.
Treg and MC cell-to-cell contact based on OX40/OX40L pairing led to downregulation of the Fyn/Gab2/PI3K pathway and inhibited MC degranulation, thereby preventing allergic inflammation.
Treg-derived TGF-β1 regulates MC activation by inter-downregulating its receptor with IL-4.
Treg-derived IL-9 promotes MC migration to allogeneic skin to promote immune tolerance. However, in different mouse models, Treg inhibited IL-9 production, resulting in enhanced IL-9-dependent MC degranulation, thereby exacerbating the inflammatory manifestations of infection.
The reverse effect of MC on Treg cells is similar to that of neutrophils. The secretion of IL-2 and TGF-β can affect the Treg/Teff ratio. MC-derived histamine inhibits the inhibition of Treg on effector T cells by signaling through the H1 receptor in vitro. MC can also drive Treg to a Th17-like phenotype through OX40/OX40L-mediated cellular contact in response to IL-33 or IL-6.
Interaction with dendritic cells
Front. Immunol.
Treg/DC crosstalk is an important pathway for Treg to maintain immune tolerance to both self and non-threatening foreign antigens.
Treg expresses CTLA-4 at high levels and competes with CD28 for its binding to CD80/CD86, thereby limiting the DC-stimulated Teff response.
Treg can also physically downregulate CD80/CD86 expression of DCs directly through trans-endocytosis or trogocytosis via CTLA-4.
In an inflammatory environment, thymic-derived Treg has also been shown to induce endocytosis of CD70 on the surface of DCs, thereby inhibiting the CD70/CD27 pathway, thereby limiting subsequent Th1 responses.
IL-10 and TGF-β secreted by Treg also inhibit the expression of proteins such as HLADR, CD80/CD86 and CD40 on the surface of DC, and also inhibit the production of pro-inflammatory cytokines such as TNF and IL-12.
In mouse models, thymic Treg secretion of IL-35 also induces tolerant DCs, increases the expression of CD11b and IL-10, and decreases MHC-II expression.
CD4+ Foxp3+ Treg can also increase secreted IL-10 levels and decrease IL-6 production by inducing LPS-activated DCs through its secreted extracellular vesicles, which in turn affect EV-mediated miR-150-5p and miR-142-3p trafficking.
Treg of other phenotypes can also have an impact on DC, such as:
FoxA1+ Treg with defective Foxp3 expression but high PD-L1 expression reduces IL-12 and IL-17 production by LPS-activated HLA-DR+ antigen-presenting cells.
In vitro production of antigen-specific Foxp3-CTLA-4+ PD-1+ ICOS+ Tr1 can modulate DCs to a tolerant phenotype with high expression of ILT3, ILT-4 and HLA-G, and can also induce the death of myeloid cell-derived antigen-presenting cells by releasing granzyme B and perforin through CD2/CD58 and CD226/CD155 cell contact.
Interaction with innate immune lymphocytes
Front. Immunol.
NK cells
Treg reduces cell killing activity and proliferation through membrane-bound TGF-β, down-regulates the activation of receptors NKG2D and NKp44 through the OX40/OX40L pathway, up-regulates and inhibits the receptors CD158a, CD158b and NKG2a, and inhibits the secretion of IL-12 and IFN-γ.
Intrahepatic Treg also inhibits NK cell degranulation and NKG2D expression in a CTLA-4-dependent manner, helping to reduce liver fibrosis.
Treg can also inhibit NK cell proliferation, cytotoxicity and IFN-γ production by secreting IL-37 and affecting its receptor IL-1R8, resulting in down-regulation of TIM-3 expression and up-regulation of PD-1 expression in NK cells.
However, in autoimmune inflammation, the role of NK cells is two-sided. On the one hand, NK cells can exert typical pro-inflammatory effects through direct cytotoxicity and production of pro-inflammatory cytokines, and at the same time, they can regulate adverse immune responses by eliminating autoreactive immune cells and producing anti-inflammatory mediators such as IL-4, IL-10, and TGF-β.
NKT cell CD4+ CD25+ Treg relies on ICAM antibody-mediated direct cell-to-cell contact to inhibit Vα24+ NKT cell proliferation, target tumor cytotoxicity, and produce cytokines such as IFN-γ, IL-4, IL-10, and IL-13.
In environments such as allergies, activated NKT cells inhibit the counterregulatory function of Treg. NKT cells can also promote the expression of the negative costimulatory receptor PD-1 and the production of IL-10 by secreting IL-4, and they also secrete IL-2 to maintain Treg survival.
γδT cellsγδT cells express a series of NK cell surface receptors, and their effector functions include lysis of target cells and production of pro-inflammatory cytokines such as IFN-γ, TNF, IL-17A, and IL-6.
In inflammation, Foxp3+ Treg reduces the proliferation of γδT cells, inhibits the production of IL-17A and IFN-γ by γδ T cells under TGF-β and IL-10-dependent conditions, and reduces its toxicity to tumor cells. These effects can be abrogated by IL-10 or TGF-β1 antibodies.
In the mouse model, CD69+ Treg inhibits the action of γδT cells to protect myocardium from inflammation by CD39 exonuclease activation, inhibits IL-17A production and reduces migration to infarcted myocardium.
In acute respiratory tract inflammation, depletion of GATA3+ Treg expressing IL-33 receptor ST2 leads to an increase in IL17-secreting gamma delta T cells and exacerbates allergic lung inflammation.
Like other innate immune effector cells, gamma delta T cells may also compete with Treg for function. For example, during autoimmune encephalomyelitis in mice, IL-23 secreted by γδ T cells reduced the number of Treg and inhibited CD4+ αβT cells. Similarly, IFN-γ secretion by γδT cells may inhibit CD4+ T cell induction of Treg differentiation, expansion, and inhibition of effector T cells.
Bibliography:
1.Ou Q, Power R and Griffin MD (2023) Revisiting regulatory T cells as modulators of innate immune response and inflammatory diseases. Front. Immunol. 14:1287465. doi: 10.3389/fimmu.2023.1287465
2.Emeka B. Okeke,et al. Deficiency of Phosphatidylinositol 3-Kinase δ Signaling Leads to Diminished Numbers of Regulatory T Cells and Increased Neutrophil Activity Resulting in Mortality Due to Endotoxic Shock. J Immunol 1 August 2017; 199 (3): 1086–1095.
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