After the identification of VDR in activated T lymphocytes, vitamin D has been proposed as a regulator of the immune system [13]. The active form of vitamin D, 25(OH)₂D₃, has an immunomodulatory effect on many components of the innate and adaptive immune systems [17]. 1,25(OH)₂D₃ regulates differentiation and maturation of subpopulations of innate immunity cells, antigen presentation and the production cytokines and chemokines. 1,25(OH)₂D₃ inhibits the inflammatory response by suppressing the expression of Toll-like receptors 2 and 4 (TLR2/4) and the secretion of pro-inflammatory mediators (IL-1, IL-6, TNF-α). In addition, the active form of vitamin D negatively regulates the differentiation, maturation and immunomodulatory capacity of dendritic cells (DCs) by reducing the expression of MHCII, CD40, CD80, CD86 and the maturation proteins CD1a, CD83 [17]. 1,25(OH)₂D₃ also inhibits the DC-mediated activation process of T cells and decreases the expression of inflammatory mediators (IL-12, IFNy in DCs) [5,20]. 1,25(OH)₂D₃ inhibits the proliferation of T lymphocytes and the production of IFNy and IL-17 and increases the secretion of IL-4 and IL-10. Thus, 1,25(OH)₂D₃ enhances the regulatory Th2 immune response and induces the differentiation of Treg cells, thereby reducing the pro-inflammatory potential of Th1 and Th17 cells.

The complex 1,25(OH)₂D₃-VDR-RXR blocks the formation of NFAT/AP-1. It is known that the formation of the NFAT/AP-1 complex is necessary for the activation of the IL-2 promoter.

The repressive effect of 1,25(OH)₂D₃ on IFNy gene transcription is due to the direct interaction of VDR-RXR with the silencer regions on the gene promoter. 1,25(OH)₂D₃ enhances the production of IL-4 by Th2 cells and potentiates the regulatory properties of Treg cells by activating the expression of the transcription factor FoxP3 [5,22].

The immunomodulatory effect of 1,25(OH)₂D₃ is also associated with an increase in IL-6 secretion, which may lead to a shift in the balance towards the Treg cell response [20,32].

1,25(OH)₂D₃ prevents IL-17 production by suppressing inflammation and Th17-mediated autoimmunity [33,34].

The mechanism of IL-17 suppression by 1,25(OH)₂D₃ is based on blocking NFAT binding to the IL-17 gene promoter, sequestration of Runx1 factor by the VDR, recruitment of histone deacetylase (HDAC) and induction of FoxP3 expression [22]. In addition, the VDR interacts with the P105/P50, P100/P52 and P65 proteins of the NF-kB factor.

In hypovitaminosis D, the addition of 1,25(OH)₂D₃ has been shown to help suppress the formation of inflammatory infiltrates and inhibit the expression of RORyt/IL-17 in spleen tissue of mice by preventing the translocation of P65 into the nucleus [35].

The stimulatory effect of 1,25(OH)₂D₃ on the production of anti-inflammatory cytokines (IL-4, IL-10) may be indirect and dependent on numerous intercellular contacts and the state of cell activation.

DCs are known to be an important target for 1,25(OH)₂D₃. Under the influence of vitamin D, their maturation is affected by transcription-mediated reprogramming of metabolic pathways (simultaneous increase in glycolysis and oxidative phosphorylation). Moreover, the mechanism for reducing IL-12 production in DCs involves binding of VDR-RXR to the NF-kB site on the IL-12p40 gene promoter. Thus, 1,25(OH)₂D₃ can alter T cell behavior by regulating DCs, causing T lymphocyte anergy [20] and converting pro-inflammatory Th1/Th17 cells into more tolerant cells (Th2/Treg cells) [21].

5. Vitamin D and T-lymphocytes

Expression of VDR has been detected in cells of innate and adaptive immunity [20]. Vitamin D exerts an immunoregulatory function by inhibiting proinflammatory cells and promoting the development of anti-inflammatory populations, thus participating in the processes of immune tolerance. Cells of the immune system express the enzyme CYP27B1 and can locally convert 25(OH)D₃ to the active form 1,25(OH)₂D₃, where it is further utilized or locally released to neighboring cells [13,14]. However, the importance of the systemic circulating level of 25(OH)D₃, which has a longer half-life, has been demonstrated [14].

The degree of activation of T lymphocytes is directly related to their phenotypic characteristics and functional potential. During their life (maturation), T cells (CD4⁺) undergo several stages of differentiation, starting with naïve (Tn) and then sequentially progressing into the group of effector cells (Teff) (including Th1, Th2, Th9, Th17, Th22 cells), central memory cells (Tcm)/memory effector cells (Tem) and terminally differentiated memory T cells (Temra) [36]. The level of VDR expression was found to be related to the activation of T lymphocyte; naive T cells are thus insensitive/resistant to vitamin D.

5.1. Th1 and Th2 Cells

Studies on obesity and DM2 have shown a significant increase in Th1 and Th17 cells and a decrease in the number and functional properties of Treg cells [6].

1,25(OH)2D3 was found to suppress IFNy production [18], blocking Th1 cell differentiation and development, against a background of increased secretion of IL-4 (which stimulates Th2 cell formation) [13].

5.2. Non-Pathogenic Th17 Cells and Treg

Obesity caused by a high-fat diet results in low secretion of Th17-associated cytokines in the intestine and adipose tissue, but high in the liver [37,38].

Non-pathogenic Th17 lymphocytes have a high intracellular content of polyunsaturated fatty acids and cholesterol esters and also a low content of saturated and monounsaturated fatty acids and triglycerides [39]. Melatonin, cholesterol, cholesterol sulfate and steroid lipids (oxysterols) have been shown to be ligands of RORα (RORyt) [40].

A distinctive feature of Th17 cells (compared to Treg cells) is the de novo synthesis of neutral fatty acids. The energy cost of this process in Th17 cells is compensated by glycolysis [41].

1,25(OH)₂D₃ has been shown to inhibit Th17 cell differentiation and stimulate Treg cell development [13]. 1,25(OH)₂D₃ inhibits the secretion of IL-17A, IL-17F, IL-22 and IL-26 [18].

5.3. Th1.17-Cells

Consumption of high-calorie foods leads to the disruption of immune cell homeostasis in the gastrointestinal tract and the formation of a pro-inflammatory pool of Th17 lymphocytes that can migrate to adipose tissue and liver. The development of an inflammatory response against a background of metabolic endotoxemia and adipocyte hypertrophy/hyperplasia can activate the plastic properties of Th17 cells, which, under similar conditions, can first transform into IL-17⁺IFNy⁺ lymphocytes and then into pathogenic Th17 cells (pTh17/Th1.17/nonclassical Th1) involved in the development of AIDs [42].

Th1.17 cells have been found to form a heterogeneous population that differs in phenotypic characteristics and cytokine-producing properties and depends on epigenetic stimuli that regulate permissive (H3K4me3) and repressive (H3K27me3) histone marks [32,43]. One of the characteristics of pTh17 lymphocytes is a high production of pro-inflammatory mediators: IFNy, TNF-α, GM-CSF and cytotoxic molecules (granzymes, perforin), together with a low secretion of IL-17, which is also reflected in the genotypic characteristics of these cells [44].

It was found that 1,25(OH)₂D₃ suppresses DC maturation and reduces the number of IL-17⁺IFNy⁺ cells during in vitro cultivation [45].

5.4. Memory T Cells

Vitamin D is an important regulator of CD4⁺ lymphocyte differentiation [13]. A link between vitamin D deficiency and an increase in the number of proinflammatory memory CD4⁺CD28 cells has been suggested [16]. In NASH, often associated with obesity, an increase in local infiltration of CD4⁺CD28 memory cells into the liver has been observed [46].

Loss of the co-stimulatory molecule CD27 (as well as CD28) by T cells (transition to the memory T cell pool) is associated with increased gene expression (mTORC1, ICC, cholesterol metabolism and glycolysis) [47].

This allows us to consider the population of Th1.17 cells that have undergone multiple antigenic stimulation as part of the memory T cell pool.

CD28^null cells are newly activated memory/effector cells equipped with combinations of adhesion molecules and chemokine receptors that mediate the invasion of liver tissue. Upon reactivation, CD4⁺CD28^null cells secrete high levels of proinflammatory cytokines TNF-a and IFNy [46]. Furthermore, pathogenic memory T cells express a multidrug resistance receptor (MDR-1 or P-glycoprotein) on the cell membrane, similar to cancer stem cells that are resistant to chemotherapy. 1,25(OH)₂D₃ decreases the drug resistance of tumor cells [51]. Vitamin D may have a similar effect on pathogenic CD4⁺CD28^null cells in inflammatory diseases and AIDs.

Vitamin D has been found to decrease TNF-a production and to have a direct anti-inflammatory effect on CD4⁺CD28^null cells that accumulate in the liver in primary sclerosing cholangitis [46].

An important finding is the extent of involvement of memory T cells, including Th1.17 cells, in peripheral blood and inflammatory foci in AIDs. Circulating memory T cells are less committed and actively respond to the anti-inflammatory effects of 1,25(OH)₂D₃ and block IL-17 and IFNy. However, memory T cells localized in areas of active inflammation are the most highly committed Th1,17 cells (probably Temra) that are resistant to the action of 1,25(OH)₂D₃ [5].

Thus, the final affiliation of memory T cells to a particular phenotype plays a central role in attenuating the anti-inflammatory effects of vitamin D. VDR, as a transcription factor, regulates the expression of genes (IL-17,IFNy) containing functional vitamin D response elements (VDRE) [52,53]. This process is regulated by genomic variations and epigenetic mechanisms that lead to specific changes in 1,25(OH)₂D₃-mediated chromatin remodeling and VDRE availability [54].

6. Hypovitaminosis D in Obesity

Based on previously obtained data, theories have been formulated that partially explain the relationship between hypovitaminosis D and obesity [55,56,57].

(1)

Volume dilution. Serum vitamin D levels decrease with increasing body size [58,59].

(2)

Sequestration of vitamin D in adipose tissue. Vitamin D (synthesized by skin, supplements/medications) becomes tightly bound in fat stores and does not enter the bloodstream in sufficient quantity to maintain serum levels of 25(OH)D₃ [55,57].

(3)

Different ability to activate vitamin D in adipose tissue of lean and obese individuals [58]. In adipocytes, high expression of the enzymes 1α-hydroxylase (mitochondrial CYP27B1) and 25-hydroxylase CYP2J2 was found [55]. However, their expression is lower in obese people compared to lean people [60].

7. Molecular Mechanism of Action of Vitamin D on T Cells under Hypoxic Conditions Associated with Obesity

In obesity, the formation of local foci of hypoxia is observed. At the same time, hypoxia activates the transcription of the factor HIF-1α, which, together with mTORC1, promotes pTh17 cell differentiation [41]. Vitamin D has been shown to suppress LPS-induced expression of HIF-1α, thereby reducing the extent of hypoxia [62].

The mTORC1 pathway is believed to play an important role in the induction of plastic properties and the formation of Th1.17 cells (with a pathogenic phenotype) [63]. The PI3K (phosphatidylinositol 3-kinase)-AKT-mTORC1-S6K axis has been described as a positive regulator of Th17 cell differentiation that induces nuclear translocation of the RORyt factor [64].

Кроме того, гипоксия и другие клеточные нарушения (повреждение ДНК, стресс эндоплазматического ретикулума, энергетический стресс) вызывают транскрипцию гена DDIT4 (транскрипт 4, индуцируемый повреждением ДНК, или REDD1). Недавние исследования показали, что связывание 1,25 (OH) ₂ D ₃ с VDR может увеличивать экспрессию гена DDIT4. Учитывая, что активация DDIT4 приводит к ингибированию mTORC1, их взаимодействие может регулироваться 1,25 (OH) ₂ D ₃ [ 65 ].

В то же время DDIT4 подавляет активность mTORC1, индуцируя комплекс TSC1 / 2, и регулирует продукцию IL-17 у пациентов с рассеянным склерозом [ 72 ].

В патологических условиях аденозинтрифосфат (АТФ) высвобождается из внутриклеточных запасов во внеклеточное пространство, где он действует как сигнал стресса (тревога, предупреждение, DAMP), связываясь с пуринергическими рецепторами. Пуринергический рецептор P2X7 (P2X7R), внеклеточный АТФ-зависимый канал, участвует в секреции провоспалительных цитокинов (которые запускают воспалительный ответ), гибели клеток и аутофагии [ 38 , 73 , 74 ].