Oleic acid increases the suppressive function of regulatory T lymphocytes

In this paper, I will share with you recently published research results that indicate the importance of fatty acids in regulating the function of regulatory T lymphocytes (Treg) in healthy persons and patients with autoimmune diseases (Pompura SL, Wagner A, Kitz A, LaPerche J, Yosef N, Dominguez- Villar M, Hafler DA Oleic acid restores suppressive defects in tissue-resident FOXP3 Tregs from patients with multiple sclerosis J Clin Invest. 2021 Jan 19; 131 (2): e138519. Doi: 10.1172 / JCI138519).

Treg is one of the subpopulations of T lymphocytes that play a key role in maintaining peripheral tolerance, preventing autoimmunity, and limiting chronic inflammatory diseases. Treg cells express FoxP3 and suppress the activity of various immune cells. Treg play key roles in maintaining homeostasis, but also in regulating the immune response to pathogenic and tumor cells.

Treg cells include heterogeneous subpopulations that have different phenotypes and functions. Treg are heterogeneous in terms of their ability to localize in specific tissues and acquire tissue-specific characteristics adapted to suppress the immune response in a given tissue. Differentiation and functions of different Treg subpopulations are regulated by different transcription factors that are activated by antigens and cytokines.
Decreased numbers or defects in Treg function exist in many autoimmune diseases such as type 1 diabetes, multiple sclerosis (MS), autoimmune hemolytic anemia (AHA), autoimmune thyroid disease (ATD), rheumatoid arthritis (RA), systemic lupus erythematosus ( SLE), Sjögren’s syndrome, systemic sclerosis and others.

1. T cell metabolism

Research in recent years indicates the importance of metabolic processes within immune cells that determine their functional characteristics. Functionally different subpopulations of T cells require different energy and biosynthetic pathways that support specific functional needs. T cell activation leads to dramatic changes in cell metabolism that are triggered to achieve optimal function of effector T lymphocytes in defense against pathogens.

Resting T cells require predominantly metabolic processes that generate ATP, while activated, proliferating T cells require metabolic processes that will provide the energy requirements of effector T lymphocytes. Upon activation, naive T cells become effector T cells that divide rapidly and change their metabolic program so that oxidative phosphorylation (OXPHOS) is replaced by aerobic glycolysis (a phenomenon known as the Warburg effect) to meet the increased need for cell energy.

Cellular metabolism is now considered crucial for T cell function and fate because it affects the development, activation, differentiation, and function of T cells. Modulation of metabolic processes in T lymphocytes could be part of novel therapeutic interventions in various diseases.

2. Treg metabolism

Treg rely heavily on an OXPHOS metabolic program that basically has the β-oxidation of fatty acids necessary for their suppressive function and stable FoxP3 expression. Cytokines that promote Treg differentiation, such as TGF-β, activate AMPK and promote β-oxidation of fatty acids and thus initiate the differentiation of naive T cells to Treg. If β-oxidation of fatty acids is inhibited, Treg differentiation is prevented, which confirms the importance of the OXPHOS metabolic pathway in maintaining Treg function.

oleic acid

3. Resident Treg maintain tissue homeostasis

The suppressive function of Treg is crucial for controlling the immune response and preventing autoimmunity. However, Treg plays a significant role in the regulation of tissue homeostasis, because Treg infiltrates various tissues not only during inflammatory conditions or injuries and is called resident Treg. Treg subpopulations found in tissues possess unique epigenetic and transcriptional profiles that allow them to fine-tune their tissue-specific functions. Resident Tregs adapt to perform functions specific to the tissue in which they are located. Treg in muscles play a role in maintaining homeostasis and tissue repair after injuries. In the skin, Treg are necessary to prevent skin lesions, hypersensitivity and atopic dermatitis. In adipose tissue, Tregs are found in visceral adipose tissue and express genes that allow these Tregs to adapt in a lipototoxic environment. However, the modalities of Treg metabolic adaptation in different tissues are largely unknown. Investigating signals that act to either promote or inhibit Treg in tissues is essential to understanding the biology of Treg.

4. The role of lipids in Treg function

In the mentioned paper, the authors hypothesized that lipids may be of crucial importance for Treg function. Considering the lipid-rich environment of most tissues, the authors believe that oleic acid plays an important role in the function of resident Tregs.

The effect of oleic acid as the most abundant free long-chain fatty acid (LCFA) on Treg function was investigated. Oleic acid enhances the metabolism of OXPHOS, which triggers fatty acid oxidation (FAO), creating a positive feedback mechanism that induces FoxP3 expression and enhances STAT5 phosphorylation (p-STAT5), which affects Treg stability and their suppressive function.

The effects of oleic and proinflammatory arachidonic acid on Treg in vitro, as well as the transcriptome profile of Treg isolated from blood and adipose tissue of healthy individuals and patients with multiple sclerosis (MS) were investigated.

The transcriptome profile of Treg gene expression isolated from peripheral blood and adipose tissue of healthy individuals was shown to be similar to that when Treg were treated with oleic acid in vitro. In contrast, the transcriptome profile of Treg patients with relapsing-remitting multiple sclerosis was similar to the profile of Treg treated with proinflammatory arachidonic acid in vitro. Finally, oleic acid concentrations were reduced in adipose tissue of patients with MS. Dysfunctional Treg in patients with MS partially regained suppressive activity when treated with oleic acid in vitro.

Some of the most important results of this research are:

  • Oleic acid upregulates fatty acid β-oxidation in Tregs
  • Oleic acid drives Treg suppression by upregulating FAO-dependent Treg genes
  • Adipose tissue–derived Tregs from healthy individuals, not patients with MS, are more similar in profile to oleic acid–treated Treg profiles
  • Treg isolated from adipose tissue of patients with MS have a similar transcriptome profile with Treg treated with proinflammatory arachidonic acid in vitro
  • There are differences in the profile of gene expression in Treg isolated from adipose tissue of healthy individuals and patients with MS
  • In vitro treatment with oleic acid partially restores defective suppressive function of Treg from patients with MS
  • Transcriptomic analysis suggests that the balance of oleic and arachidonic acid in the extracellular environment modulates the Treg phenotype

Healthy individuals and patients with MS have different lipid composition in plasma and visceral adipose tissue — individuals with MS have decreased oleic acid levels, the finding that implies different LCFA composition in healthy individuals and patients with autoimmune diseases.

This paper defines a new mechanism by which lipids in tissues trigger cell-specific metabolic programs that establish positive feedback to increase Treg stability and function by regulating CD25/STAT5/FoxP3 expression. Treg from patients with MS in the presence of oleic acid in vitro restored suppressive activity, the findings that show the importance of fatty acids in suppressing inflammatory signals in tissues which may be important in the development of drugs to treat autoimmune diseases by correcting defective Treg functions.

Further studies of the relationship between lipid composition, obesity and inflammation in adipose tissue and the risk of autoimmune diseases are needed to better understand the role of lipids and Treg biology.

If you have questions, comments and suggestions for topics I will be happy to answer.

Literature

  1. Pompura SL, Wagner A, Kitz A, LaPerche J, Yosef N, Dominguez-Villar M, Hafler DA. Oleic acid restores suppressive defects in tissue-resident FOXP3 Tregs from patients with multiple sclerosis. J Clin Invest. 2021 Jan 19;131(2):e138519. doi: 10.1172/JCI138519
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