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Review
. 2022 Feb 25:13:828191.
doi: 10.3389/fimmu.2022.828191. eCollection 2022.

Metabolism Characteristics of Th17 and Regulatory T Cells in Autoimmune Diseases

Yan Qin  1 , Chong Gao  2 , Jing Luo  1
Affiliations
Review

Metabolism Characteristics of Th17 and Regulatory T Cells in Autoimmune Diseases

Yan Qin et al. Front Immunol. .

Abstract

The abnormal number and functional deficiency of immune cells are the pathological basis of various diseases. Recent years, the imbalance of Th17/regulatory T (Treg) cell underlies the occurrence and development of inflammation in autoimmune diseases (AID). Currently, studies have shown that material and energy metabolism is essential for maintaining cell survival and normal functions and the altered metabolic state of immune cells exists in a variety of AID. This review summarizes the biology and functions of Th17 and Treg cells in AID, with emphasis on the advances of the roles and regulatory mechanisms of energy metabolism in activation, differentiation and physiological function of Th17 and Treg cells, which will facilitate to provide targets for the treatment of immune-mediated diseases.

Keywords: Th17 cells; autoimmune disease; gut microbiota; immunometabolism; regulatory T cells; single-cell metabolism.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The differentiation of naive CD4+T cell into Th17 and Treg cells. ROR-γt and Foxp3, the respective lineage-specific transcription factors for Th17 and Treg cells. IL-6 or IL-1β induce the differentiation of T cells into Th17 cells through STAT3 or mTOR in the presence of low TGF-β, however, IL-2 critically drives high TGF-β-treated CD4+ cells to differentiate into Foxp3+ Treg cells via JAK-STAT. The inflammatory environment controls the balance between Treg and Th17 cell differentiation cellular metabolism controls T cell lineage choices. TGF-β, transforming growth factor-beta; IL, interleukin; JAK, Janus kinase; STAT, signal transducer and activator of transcription; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; RORγt, retinoid-related orphan receptor-γt; Foxp3, forkhead box P3; Th, T-helper cell; Treg, regulatory T cell; GM-CSF, granulocyte-macrophage colony stimulating factor; CXCL1, chemokines; CCL20, chemokines.
Figure 2
Figure 2
Potential mechanisms and therapeutic target of Th17/Treg metabolic homeostasis. Upon antigen stimulation, cellular metabolism controls T cell lineage choices. During T cell activation, CD28 up-regulates glycolysis by promoting the increase of c-myc and the Glut1 in CD4+ T cells. The increase of glycolysis induced by CD28 was important for differentiating of Th17 cells. The activation of mTORC1 is mainly mediated by the PI3K/Akt and LKB1-AMPK, thus enhancing glycolysis and predisposing naïve T cells to differentiate into inflammatory Th17 cell. Over-activation of mTOR, Myc and HIF1 promote glycolysis and weaken suppressive activity of Treg cell, and ultimately lead to the loss of suppressive function in inflammatory conditions. In turn, Foxp3 inhibited c-Myc in Treg cells. Also, the lipid metabolism affected the differentiation of CD4+ T cells, and the differentiation of Th17 cells required FAS, but Treg cell was rely on FAO. Inhibition of mTOR can result in the elevated FAO and promote Treg differentiation. In addition, rapamycin-mediated inhibition of mTOR blocks glycolytic activity and increases the FAO. Metformin, an AMPK agonist, which exerts anti-inflammatory effects on CD4+ T cells and induce Treg expansion and lipids alterations. The use of rapamycin and metformin lead to pro-oxidative effects following CD4+T cell stimulation. APC, antigen presenting cell; CD, cluster of differentiation; GLUT, Glucose transporter; AKT, proteinserine-threonine kinase; LKB-1, liver kinase B-1; AMPK, Cyclic Adenosine monophosphate-activated protein kinase; HIF-1α, hypoxia-inducible factor-1; ACC, acetyl-CoA carboxylase; SREBP1, sterol regulatory element-binding protein 1; FAO, fatty acid oxidation; FAS, fatty acid synthesis.
Figure 3
Figure 3
The IL-2/IL-2R signaling pathways control the lineage choice of Th17 and Treg cells. The co-expression of IL-2Rα, IL-2Rβ and γc is essential for IL-2 binding to cell. IL-2 regulation of Treg cells is mediated by the PI3K-Akt and JAK-STAT5 pathway. JAK-STAT5 pathway promotes Treg cells differentiation, and inhibiting transcription of the IL-17, thereby suppressing Th17 cell. In addition, IL-2 can activate mTOR through PI3K-AKT and promote the differentiation of CD4+ T into Th17 cells. IL-2R, interleukin-2 receptor; P, phosphorylate; PDK, phosphoinositide-dependent kinase.
Figure 4
Figure 4
Tying microbiota metabolism to Th17/Treg balance. SCFAs produces by gut microbiota metabolizing dietary fiber can serve as a substrate for FAO, further producing acetyl-CoA, which provides fuel for TCA and OXPHOS. SCFAs strengthen the extrathymic generation of Treg cells by inducing Foxp3 in HDAC-dependent mode, while LCFAs promote the generation of pathogenic Th17 cells via the MAPKs p38 and JNK1. In addition, SCFAs could indirectly induce the production of ATP and the depletion of AMP, leading to the activation of mTOR in B cell and the generation of immunoglobulin. SCFAs, short-chain fatty acids; LCFAs, long-chain fatty acids; ATP, Adenosine-triphosphate; AMP, Cyclic Adenosine monophosphate; HDAC, histone deacetylase; MAPKs, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase; AMPKK, AMPK kinase; TCA, tricarboxylic acid cycle; OXPHOS, oxidative phosphorylation.
Figure 5
Figure 5
The tryptophan-kynurenine pathway and autoimmune. Trp can be metabolized to Kyn by IDO, and eventually lead to the generation of the NAD+ and the activation of mTOR. Therapeutic intervention with NAC reverses the accumulation of Kyn and the activation of mTOR, and induces autophagy and restores Treg functions. TNF-α, tumor necrosis factor-α; IFN-γ, interferon-γ; IDO, indoleamine-pyrrole 2,3-dioxygenase; NAC, N-acetylcysteine; NAD+, nicotinamide adenine dinucleotide; CTLA-4, cytotoxic T-lymphocyte-associated protein 4.
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