Control of T-cell immunity by fatty acid metabolism

Jaemin Kim; Yoosun Lee; Yeonseok Chung

doi:10.6065/apem.2448160.080

Ann Pediatr Endocrinol Metab > Volume 29(6); 2024 > Article

Kim, Lee, and Chung: Control of T-cell immunity by fatty acid metabolism

Review Article

Annals of Pediatric Endocrinology & Metabolism 2024;29(6): 356-364.

Published online: December 31, 2024

DOI: https://doi.org/10.6065/apem.2448160.080

Control of T-cell immunity by fatty acid metabolism

Jaemin Kim^1,^2,^*

, Yoosun Lee^1,^2,^*

, Yeonseok Chung^1,²

¹Laboratory of Immune Regulation, Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea

²BK21 Plus Program, College of Pharmacy, Seoul National University, Seoul, Korea

Address for correspondence: Yeonseok Chung Laboratory of Immune Regulation, Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea Email: yeonseok@snu.ac.kr

^* These authors contributed equally to this study as co-first authors.

Received July 8, 2024 Revised November 19, 2024 Accepted December 3, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Fatty acids play critical roles in maintaining the cellular functions of T cells and regulating T-cell immunity. This review synthesizes current research on the influence of fatty acids on T-cell subsets, including CD8⁺ T cells, T_H1, T_H17, T_reg (regulatory T cells), and T_FH (T follicular helper) cells. Fatty acids impact T cells by modulating signaling pathways, inducing metabolic changes, altering cellular structures, and regulating gene expression epigenetically. These processes affect T-cell activation, differentiation, and function, with implications for diseases such as autoimmune disease and cancer. Based on these insights, fatty acid pathways can potentially be modulated by novel therapeutics, paving the way for novel treatment approaches for immune-mediated disorders and cancer immunotherapy.

Keywords: Fatty acids, Fatty acid metabolism, Fatty acid signaling, Immunometabolism, T-cell differentiation

Highlights

· Fatty acids regulate T-cell immunity by modulating signaling pathways, cell structure, metabolism, and epigenetics.

· Fatty acids impact T-cell activation, differentiation, and function, contributing to autoimmune diseases and cancer.

· Targeting fatty acid pathways offers potential for innovative therapies in immune-mediated diseases.

Introduction

Lipids and fatty acids play crucial roles in maintaining basic cellular functions. They are major components of cell membranes, essential for preserving cell structure, and also serve as a vital energy source for cells. This holds true even for immune cells, with recent research suggesting that fatty acids and lipid metabolism directly influence the activity and balance of T-cell immunity, impacting disease development. For instance, fatty acid uptake is essential for the early activation and proliferation of CD4⁺ T cells, and is dependent on mTORC1-PPARγ (mammalian target of rapamycin complex 1-peroxisome proliferator-activated receptor gamma) pathways [1]. Consequently, fatty acids are emerging as pivotal regulators of T-cell function.

Fatty acids can regulate cellular activity through various mechanisms (Fig. 1). First, they can directly modulate the activity of specific signaling molecules, thereby regulating the secretion of various cytokines. A prominent example of lipid-involved signaling is IP₃-Ca²⁺ influx signaling, which plays a crucial role in activating enzymes and triggering signaling pathways involved in cell activation. Second, lipids can induce metabolic reprogramming by serving as an energy source for cellular metabolism, thereby regulating cellular activity. Fatty acids enter mitochondria via the enzyme carnitine palmitoyltransferase 1 (CPT1) and undergo fatty acid oxidation (FAO) to generate acetyl-CoA, which can be utilized in the tricyclic acid (TCA) cycle to produce adenosine triphosphate (ATP). Etomoxir, frequently used to inhibit FAO, acts as a CPT1 inhibitor. FAO is a metabolic pathway predominantly utilized by regulatory T cells (T_reg) or memory T cells (T_mem) [2,3]. Third, fatty acids can alter cellular structure. They can regulate membrane fluidity via insertion into the membranes of cellular organelles such as cell membranes, lipid droplets, endoplasmic reticulum (ER), and the Golgi apparatus. They can also modulate activity by increasing the connectivity between mitochondria and other cellular organelles, such as the ER [4,5]. Lastly, fatty acids can epigenetically regulate the expression of specific genes by modulating histone modification [6].

Fatty acids are generally classified into short-chain fatty acids (SCFAs<C₆), medium-chain fatty acids (MCFAs, C₆–C₁₂), long-chain fatty acids (LCFAs, C₁₃–C₂₀), and very-long-chain fatty acids (VLCFA>C₂₀), based on their chain length. LCFAs can be further separated into saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and poly-unsaturated fatty acids (PUFAs) based on the number of unsaturated bonds. These classifications directly relate to their structure and function. With their diverse structures, various fatty acids can act on different target molecules, inducing a wide range of cellular responses. Fatty acids undergo de novo synthesis from acetyl-CoA by the enzyme acetyl-CoA carboxylase 1 (ACC1) and adopt different configurations with the aid of enzymes like stearoyl-CoA desaturase (SCD) and fatty acid synthase (FASN) that alter their unsaturation levels or lengths. These metabolic processes occur actively within cells and are regulated by key proteins such as sterol regulatory element-binding protein and liver X receptor (LXR).

Due to their high lipid solubility, free fatty acids can enter cells through simple diffusion or via fatty acid translocase, also known as CD36 [7]. Additionally, G-protein coupled receptor subtypes known as free fatty acid receptors (FFARs) on cellular membranes can directly mediate signal transduction in response to fatty acids. Well-known FFAR types include FFAR1 through FFAR4, with SCFAs acting on FFAR2 (GPR43) and FFAR3 (GPR41), and MCFAs and LCFAs acting on FFAR1 (GPR40) and FFAR4 (GPR120). Plasma-free fatty acids are transported bound to albumin, which also acts as a buffer for fatty acids. In contrast, within cells, fatty acid-binding proteins (FABPs) serve as important binding partners for fatty acids. In mammals, there are 9 known types of FABPs (FABP1–FABP9), with different subtypes present in different tissues [8,9].

Although the impact of fatty acids on immune cells is less well understood than their effects on other organ systems like the cardiovascular system, recent research has increasingly focused on this area. In this review, we summarize the regulatory roles of fatty acids in different T-cell subsets with regard to intracellular signaling pathways and metabolism, as well as their associations with diseases.

T_H1 and T_H2 cells

T_H1 cells orchestrate an increased cell-mediated immune response to infection, especially against intracellular pathogens, by secreting cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). They recruit phagocytic macrophages and inflammatory immune cells and contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and inflammatory bowel disease (IBD) when dysregulated. The profile of fatty acids has been examined in several T_H1-related diseases, but the interplay between fatty acids and T_H1 cells has not yet been extensively studied.

In RA, where TNF-α is one of the principal drivers, alterations in the lipid profile have been observed to correlate with T_H1 response and clinical disease severity. RA patients demonstrate significantly lower levels of palmitic, palmitoleic, oleic, arachidonic, eicosapentaenoic, and docosahexaenoic acid (DHA), while their levels of IFN-γ, CCL2, and CXCL10 are elevated relative to healthy subjects [10]. In vitro experiments conducted with peripheral blood mononuclear cells from RA patients revealed that stearic acid enhances IFN-γ secretion, whereas eicosapentaenoic acid (EPA) and DHA had an inhibitory effect on IFN-γ production. However, establishing a direct link between serum lipid levels and disease severity is challenging.

Type 1 diabetes (T1D) involves autoimmune attacks that lead to the destruction of pancreatic β cells. In T1D patients, supplementation with DHA and EPA, which are ω-3 PUFAs, has a beneficial effect [11]. In nonobese diabetic mice, dietary supplementation with DHA and EPA significantly reduced the occurrence of T1D, decreased the frequency of T_H1 cells, and lowered levels of IFN-γ and TNF-α, Conversely, a diet enriched with arachidonic acid promoted the secretion of IFN-γ and TNF-α. Furthermore, lentivirus-mediated expression of Mfat-1, an ω-3 fatty acid desaturase, improved blood glucose and insulin levels, and prevented the progression of autoimmunity and lymphocyte infiltration into regenerated islets.

SLE is an autoimmune condition characterized by the prominent presence of autoantibodies and IFN signatures [12]. In comparison to healthy donors, SLE patients exhibit elevated levels of T-bet⁺ effector cells, which produce excessive amounts of IFN-γ, and a lower number of T_reg cells [13]. In vitro differentiation using memory CD4⁺ cells obtained from SLE patients revealed that inhibiting fatty acid synthesis (using C57, an FASN inhibitor) suppressed IFN-γ production and upregulated Foxp3 expression. In summary, fatty acid synthesis contributes to the heightened IFN-γ production by memory CD4⁺ T cells in SLE patients.

T_H2 cells are responsible for the humoral immune response against helminths, especially in the skin or mucosal barriers such as those found in the respiratory and digestive tracts. When these cells are hyperactivated, they can trigger chronic inflammatory reactions, for instance, asthma or allergy.

In asthma, NRF2, a transcription factor essential for antioxidant responses, has been shown to play a critical role in regulating T_H2-cell function. NRF2 is crucial for the differentiation of polyfunctional T_H2 cells, driving optimal oxidative phosphorylation and glycolysis. Interestingly, while NRF2 deficiency does not impair fatty acid uptake, it significantly affects fatty acid metabolism and lipid oxidation, indicating that NRF2 is vital for maintaining the metabolic fitness of T_H2 cells. This disruption in fatty acid metabolism underlines the importance of NRF2 in ensuring the proper function and polyfunctionality of T_H2 cells in immune responses [14].

Furthermore, SCFAs such as acetate (C2), propionate (C3), and butyrate (C4) have been discovered to suppress T_H2 responses, consequently reducing allergic lung inflammation [15]. Microbiome profile alterations due to vancomycin intake can lead to allergic airway reactions [16]. Dietary SCFA supplementation was shown to significantly decrease the levels of immune cells and eosinophils in the lung airways as well as serum IgE concentration, both of which were elevated by vancomycin intake. Butyrate was shown to attenuate interleukin (IL)-4 production by CD4⁺ cells, as well as the expression of a chemotaxis marker (CCL19) and activation markers (CD80 and CD86) on dendritic cells.

T_H17 cells

T_H17 cells, which are a subset of CD4 T cells, play a crucial role in host defense and mucosal immunity by producing IL-17 [17,18]. However, they are also recognized as the main drivers of autoimmune diseases such as MS, RA, and IBD [19,20]. During the differentiation and activation of T_H17 cells, they rely on aerobic glycolysis and fatty acid synthesis [21,22].

Notably, fatty acid biosynthesis is indispensable for T_H17 cell differentiation. ACC1 is a key enzyme in fatty acid biosynthesis, playing a key role in the formation of LCFAs. Acaca-/- T cells fail to properly differentiate into T_H17 cells and ACC1 inhibition has the same effect [23,24]. This has been ascribed to the impaired nuclear localization of retinoic acid-related orphan receptor gamma t (RORγt), despite no observable alteration in RORγt expression levels. Furthermore, ACC1 deficiency protected against experimental autoimmune encephalomyelitis (EAE) and ACC1 inhibition delayed EAE onset and reduced severity. Similarly, FASN is crucial for the differentiation and function of T_H17 cells. Inhibition of FASN reduced the generation of pathogenic T_H17 cells and ameliorated the disease severity of EAE [25].

Fatty acid metabolism plays a crucial role in psoriasis, an autoimmune skin disease closely associated with T_H17 cells. Psoriasis involves significant downregulation of fatty acid biosynthesis and metabolic pathways, with key enzymes like FASN, FADS1, and ELOVL3 showing decreased expression in psoriatic skin, while ACC1 and SCD are upregulated. Similar patterns have been observed in murine models, and activation of LXR and PPARγ has been demonstrated to alleviate psoriasis symptoms by restoring fatty acid metabolism and reducing T_H17-mediated inflammation. Additionally, IL-13-producing innate lymphoid cells (ILCs) are crucial for maintaining tonic type 2 immunity, which helps regulate lipid homeostasis and resist psoriasis. These findings suggest that restoring fatty acid metabolism through LXR and PPARγ activation and modulating IL-13-producing ILCs could facilitate management of psoriasis by modulating T_H17 cell activity and pathogenicity [26].

Intracellular fatty acid composition determines the pathogenicity of T_H17 cells. CD5L (CD5 antigen-like), as a soluble protein, is primarily expressed in nonpathogenic T_H17 cells, where it regulates the pathogenicity of T_H17 cells by regulating the SFA/PUFA balance [27]. CD5L deficiency shifts nonpathogenic T_H17 cells towards a pathogenic phenotype, accompanied by alterations in lipidome composition. This altered lipid profile impacts the availability of RORγt ligands and expression of RORγt target genes.

FABPs, especially FABP 3-5, are abundantly expressed in T_H17 cells [9]. Fabp5-/- T cells exhibit reduced expression of RORγt, attributed to the heightened activity of PPARγ, a well-known repressor of T_H17-cell differentiation [28]. Consequently, elevated PPARγ activity suppresses STAT3 activation, leading to the reduction of T_H17 cell differentiation.

SCFAs such as acetate, propionate, and butyrate, which are byproducts of bacterial fermentation in the gut, exert immunomodulatory effects [29]. They shape the gastrointestinal immune system and have a profound impact on adaptive immunity. Acetate and propionate can directly promote T_H17-cell differentiation [30,31]. The effect of SCFAs on T_H17-cell differentiation is independent of GPR41 and GPR43. Instead, SCFAs exert their influence through inhibition of histone deacetylases (HDACs) and by enhancing the mTOR-S6K pathway. In a Citrobacter rodentium infection model, administration of acetate led to an increase in T_H17-cell populations. Conversely, in anti-CD3-induced inflammation models, SCFAs reduced inflammation through an IL-10-dependent mechanism, suggesting a dual role in promoting both effector and regulatory T-cell functions depending on context [31]. The effects of butyrate on T_H17-cell differentiation are controversial, with different outcomes reported across studies [31,32]. Considering that butyrate promotes T_reg differentiation, it is plausible that butyrate may reduce T_H17-cell differentiation. Pentanoate (C₅) was shown to effectively inhibit the proliferation of and IL-17A production by T_H17 cells, while promoting IL-10 expression and suppressing T_H17-associated gene expression [33]. Furthermore, pentanoate treatment ameliorated EAE and inhibited the generation of intestinal T_H17 cells. These effects were attributed to pentanoate's HDAC inhibitory activity and metabolic reprogramming, which included enhancing glycolysis. In conclusion, both fatty acids and their metabolism play pivotal roles in the biology of T_H17 cells.

LCFAs enhance the differentiation and proliferation of T_H1 and T_H17 cells. By consistently decreasing the levels of SCFAs in the gut, LCFAs lead to the expansion of pathogenic T_H1 and T_H17 cell populations, thereby exacerbating disease in EAE [34].

Cytosolic acetyl-CoA is the substrate for fatty acid and sterol biosynthesis, thereby promoting the generation of lipids. ATP-citrate lyase (ACLY), which converts citrate to acetyl-CoA in the cytosol, is crucial not only for the epigenetic regulation of gene expression but also for initiating de novo fatty acid synthesis. 2-Hydroxy citrate (ACLY inhibitor) significantly ameliorates EAE and reduces inflammatory cytokine production in both murine and human T_H17 cells [35]. This effect has been attributed to the lowered levels of acetyl-CoA in ACLY-deficient T_H17 cells, which results in reduced acetylation of histones at crucial cytokine genes, thereby altering T_H17-mediated immune responses.

T_reg cells

T_reg cells, a subset of CD4⁺ T cells expressing Foxp3, play a crucial role as regulators of the immune system, ensuring immunological tolerance and maintaining homeostasis by suppressing excessive immune responses [36,37]. Unlike effector CD4⁺ T cells such as T_H1, T_H2, and T_H17 cells, which primarily depend on aerobic glycolysis, induced T_reg (iT_reg) cells not only utilize FAO for their energy needs but also for their differentiation process [38].

CPT1, a critical enzyme in FAO, facilitates the transport of LCFA into the mitochondria for energy production. Contrary to previous studies, CPT1-mediated LC-FAO is largely dispensable for T-cell activation, including the generation of CD8⁺ T_mem cells and T_reg cells. CD4⁺ T cells and Foxp3⁺ T_reg cells with deletion of Cpt1a exhibited normal frequencies and total numbers of T_reg cells across different tissues, with no decrease in their suppressive capacity. Additionally, in vitro T_reg differentiation was not affected by the lack of CPA1, suggesting that the development and function of T_reg cells can occur independently of the CPT1-mediated metabolic pathway. Hence, the fact that CPT1-mediated LC-FAO is not essential for T_reg cells suggests a need for further research into how T_reg cells utilize fatty acids to regulate their functions and differentiation [39].

Within the intestinal environment, T_reg cells are pivotal in moderating inflammatory reactions [40]. As previously mentioned, SCFAs increase both the frequency and number of colonic T_regs in germ-free mice when administered through drinking water, primarily by enhancing the expression of Foxp3 and IL-10, key markers of T_reg immunosuppressive function. This effect is mediated via GPR43, as T_reg-cell expansion and function are absent in GPR43-deficient mice, indicating the importance of this receptor-dependent mechanism. Additionally, SCFAs inhibit HDACs, particularly HDAC₆ and HDAC9, thereby enhancing histone acetylation and further promoting Foxp3 expression and T_reg suppressive capacity [41]. This is particularly evident in mice exposed to propionate, which not only boosts Foxp3 and IL-10 expression but also augments the proliferative capacity of T_reg cells. These findings highlight how SCFAs regulate T_reg-cell function through both receptor-dependent signaling and epigenetic modulation [30].

Butyrate not only promotes iT_reg-cell generation by upregulating histone acetylation but also directly influences FAO, a metabolic pathway essential for iT_reg-cell differentiation. This dual role of butyrate is facilitated through the conversion of butyrate into butyryl-CoA by acyl-CoA synthetase short-chain family member 2 (ACSS2), which in turn up-regulates the activity of CPT1 [42]. This butyrate-ACSS2-CPT1 axis represents a novel mechanism by which dietary components can modulate immune functions, suggesting that dietary interventions could be a viable approach to manipulate iT_reg-cell functions and treat autoimmune diseases.

Oleic acid (OA) stands out as a key fatty acid for its ability to provide protective effects in MS. OA enhances FOXP3 expression and boosts T_reg suppressive capabilities, partially restoring their function in MS patients [43]. Additionally, OA levels were found to be reduced in the adipose tissues of MS patients compared to healthy individuals, suggesting a potential link between altered fatty acid composition and autoimmune disease pathogenesis.

SCD1 is an enzyme that plays a key role in the synthesis of monounsaturated fatty acids from SFAs, notably OA, impacting various cellular processes including lipid metabolism and the inflammatory response. The absence of Scd1 in mice influences the differentiation of naive CD4⁺ T cells toward T_reg during EAE development. Scd1 deficiency enhances T_reg frequency while reducing T_H17-cell levels in the central nervous system, contributing to EAE resistance [44,45]. Moreover, increased T_reg-cell populations in Scd1-/- mice originate from enhanced differentiation of peripheral T_reg cells rather than altered thymic selection. Notably, thymocytes developing in Scd1-/- thymic microenvironments exhibit a predisposition toward T_reg-cell differentiation, mediated by altered fatty acid composition, particularly reduced levels of OA.

FABP5 has been shown to be more highly expressed in T_reg cells than naive CD4⁺ T cells. The absence of FABP5 in T_reg cells causes mitochondrial changes, characterized by decreased OXPHOS, impaired lipid metabolism, and loss of cristae structure. Inhibition of FABP5 in T_reg cells triggers the release of mitochondrial DNA, leading to cGAS-STING-dependent type I IFN signaling. This signaling pathway induces the production of IL-10 and enhances the suppressive activity of T_reg cells [9].

T_FH cells

T follicular helper (T_FH) cells are found in B-cell follicles and are involved in the formation of the germinal center (GC) and in B-cell selection. Dysregulation of this subset is responsible for the pathogenesis of immune diseases such as SLE, RA, and T1D [46-49]. Although there are not many research papers on the direct effects of individual fatty acids on T_FH, this population of cells is highly affected by lipid byproducts and lipid metabolism.

Atherogenic dyslipidemia triggers the differentiation of autoimmune CXCR3⁺ T_FH cells while inhibiting follicular regulatory T cells, in turn aggravating SLE disease severity. The underlying mechanism is that, under atherogenic conditions, DCs overproduce IL-27 in response to TLR4 upregulation, thereby promoting autoimmune and immunization-induced GC reactions, while LXRs negatively regulate IL-27 production [50]. Beyond DCs, LXR also serves as a crucial negative regulator of T_FH-cell differentiation [51].

Furthermore, phosphatidyl ethanolamine (PE), located in the outer layer of the plasma membrane, uniquely controls T_FH-cell function by regulating CXCR5 expression. CDP-ethanolamine pathway, which mediates the de novo synthesis of PE, blocks the degradation and internalization of CXCR5. Moreover, disrupting Pcyt2, a key component of the CDP-ethanolamine pathway, impaired not only T_FH-cell differentiation but also humoral immune responses. This example demonstrates that specific lipid molecules can play a crucial role in T-cell differentiation [52].

Inhibition of SCD results in increased ER stress and enhanced T_FH-cell apoptosis both in vitro and in vivo [53]. As such, SCD plays an important role in maintaining the intracellular balance between SFAs and MUFAs, revealing a possible link between fatty acid metabolism and cellular and humoral responses induced by immunization or potentially, autoimmunity.

CD8⁺ T cells

CD8⁺ T cells directly eliminate abnormal cells, including virus-infected and cancer cells, by releasing cytotoxic molecules such as perforin and granzymes. These cells serve as key effectors of antitumor immunity within the tumor microenvironment (TME). An obese TME induced by a high-fat diet not only inhibits the infiltration and effector function of CD8⁺ T cells but also reduces responsiveness to programmed cell death protein1 inhibitor therapy [54]. In the TME of pancreatic ductal adenocarcinoma (PDA), lipid accumulation occurs during progression and leads to immunosuppression [55]. Interestingly, specific LCFAs, including palmitamide, were found to drive dysfunction in CD8⁺ T cells as evidenced by decreased proliferation and secretion of effector molecules such as IFN-γ, TNF-α, and granzyme B. Subsequently, various fatty acids have been identified as potent effector mediators of CD8⁺ T cells. For example, linoleic acid, which does not accumulate in the PDA TME, is abundant in plasma and enhances CD8⁺ T-cell potency by improving metabolic fitness [5]. In the cited study, linoleic acid strengthened ER-mitochondria contact when incorporated into intracellular membranes, thereby enhancing the memory phenotype and antitumor cytotoxicity of CD8⁺ T cells.

The multifaceted impacts of fatty acids on CD8⁺ T-cell function are likely due to their effects on diverse regulatory mechanisms, some of which will be introduced in this section. First, transvaccenic acid, which is found at high levels in ruminant-derived dairy products, enhances CD8⁺ T-cell function by antagonizing the SCFA agonist of GPR43, which plays an important role in the suppression function of T_reg. Therefore, it subsequently triggers activation of the cAMPK–PKA-CREB axis, promoting effector CD8⁺ T-cell function and antitumor immunity.56) Second, saturation of phosphoinositide acyl chains in cellular membranes enhances CD8⁺ effector T-cell survival and function. Assisted by glycolysis, saturated phosphatidylinositol phosphate is incorporated into supportive lipid rafts that can rapidly recruit phospholipase C-γ, supporting CD8⁺ T-cell activation [4]. Third, acetyl-CoA, the most abundant metabolite resulting from FAO, promotes OXPHOS and epigenetically modifies histone acetylation of IFN-γ, thereby boosting CD8⁺ T-cell effector function [6]. FAO is also involved in TNF receptor-associated factor 6 (TRAF6) signaling and the generation of memory CD8⁺ T cells [3].

The accumulation of fatty acids in the TME is thought to suppress the effector function of CD8⁺ T cells [57]. Research is currently underway to identify specific fatty acids that can boost CD8⁺ T-cell effector function and elucidate the underlying mechanisms, which should facilitate advances in anticancer therapy.

Conclusions

Activation of naive T cells is strictly regulated by 3 sequential signals. These are (1) TCR recognition of a cognate antigen presented by major histocompatibility complex receptors; (2) costimulation by the antigen-presenting cell; and (3) stimulation by cytokines that direct T-cell differentiation and proliferation [58]. Recent studies suggest that nutrients like glucose, amino acids, and fatty acids surrounding T cells influence their differentiation, activation, and survival; this has been referred to as "signal 4" [59]. It is essential to uncover how signal 4 impacts immune cells in different contexts, including cancer, infections, autoimmune diseases, and specific tissue environments.

The findings presented in this review emphasize the potential of targeting fatty acid pathways for therapeutic intervention (Fig. 2). For instance, modulation of SCFA production by the gut microbiota or dietary fatty acid supplementation could serve as a strategy to enhance T_reg function or suppress pathogenic T_H17 responses in autoimmune diseases. Similarly, manipulating fatty acid metabolism in the TME offers new avenues to overcome T-cell exhaustion and improve antitumor immunity.

Looking ahead, future research should further explore the effects of fatty acids and their metabolites on T-cell biology, as well as their potential applications in immunotherapy. Investigating how specific fatty acids influence T-cell subsets across different tissue environments could yield valuable insights for developing tailored therapeutic strategies. Such efforts will not only expand our understanding of immunometabolism, but also pave the way for innovative treatment of immune-mediated diseases.

Notes

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

This work was supported by research grants from the Leader Research Program (2020R1A3B207889011) and Basic Science Research Program (2022R1A6A1A03046247) funded by the National Research Foundation, and by Ministry of Health and Welfare of Korea (RS-2024-00432867).

Author Contribution

Conceptualization: JK, YL, YC; Funding acquisition: YC; Visualization: JK, YL; Writing - original draft: JK, YL; Writing - review & editing: YC

ACKNOWLEDGMENTS

We thank all Chung laboratory members for their discussion and suggestions. Figures were created with the help of BioRender.com.

Fig. 1.

Fatty acid metabolism in T cells. Free fatty acids enter immune cells either directly through simple diffusion or via CD36. Once inside the cell, fatty acids bind to proteins such as fatty acid-binding proteins (FABPs) that facilitate their transport. Alternatively, fatty acids can signal directly through cell surface receptors known as free fatty acid receptors (FFARs), where short-chain fatty acids (SCFAs) are known to act on FFAR2 and FFAR3, while MCFAs and LCFAs act on FFAR1 and FFAR4. Within the cell, (1) fatty acids enter the mitochondria via CPT1, where they undergo fatty acid oxidation (FAO), are broken down into acetyl-CoA, and enter the TCA cycle to produce adenosine triphosphate. (2) Fatty acids can also be incorporated into plasma membranes such as ER or cell membranes, regulating their fluidity or interaction with other cellular components. (3) Within T cells, fatty acids are modified by many different enzymes (e.g., ACC1, FAS, SCD) to form a wide variety of lipids such as phosphatidic acid (PA), lysophosphatidic acid (LPA), and phosphatidylinositol bisphosphate (PIP2). Fatty acids are modified by enzymes like desaturases to produce diverse lipid forms. All intermediates and products generated during intracellular fatty acid metabolism can epigenetically, structurally, or through specific signaling pathways, induce various changes in T cells. This positions fatty acids as novel mediators of immune diseases, including autoimmune disorders and cancer. SCFA, shortchain fatty acid; MCFA, medium-chain fatty acid; LCFA, long-chain fatty acid; cAMP, cyclic adenosine monophosphate; PLC, phospholipase C; IP₃, inositol 1,4,5-trisphosphate; ACC, acetyl-CoA carboxylase; FASN, fatty acid synthase; SCD1, stearoyl- CoA desaturase 1; SFA, saturated fatty acid; MUFA, monounsaturated fatty acid; PUFA, poly-unsaturated fatty acid; LXR, liver X receptor; SREBP, sterol regulatory element-binding protein; PPAR-γ, peroxisome proliferator-activated receptor gamma; mTORC, mammalian target of rapamycin complex.

Fig. 2.

Immunoregulation of CD4⁺ and CD8⁺ T cells by fatty acids. Dietary supplementation with ω-3 PUFAs decreases the frequency of T_H1 cells and their effector cytokines in type 1 diabetes, and the serum lipid profiles are altered in SLE and RA patients. SCFA supplementation alleviates vancomycin-induced allergic asthma by downregulating T_H2 immune responses, yet fatty acid immunometabolism remains largely unexplored in T_H1 and T_H2 cells. In T_H17 cells, genes related to fatty acid metabolism (e.g., ACC1, ACLY, FASN), intracellular proteins (e.g., FABP, CD5L), and intracellular fatty acid composition critically regulate differentiation and effector functions. T_reg-cell function is well-documented to be promoted by SCFAs and these cells actively utilize FAO for their energy needs. In T_FH cells, CXCR5 expression is uniquely controlled by phosphatidylethanolamine (PE) and its de novo synthesis pathway, governed by the gene Pyct2. LCFA accumulation in the tumor microenvironment drives CD8⁺ T-cell dysfunction, but individual fatty acids or lipid subtypes that can potentiate CD8⁺ T cells are currently being researched. DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; PUFA, poly-unsaturated fatty acid; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis; IFN-γ, interferon-gamma; TNF-α, tumor necrosis factor-alpha; IL, interleukin; PCYT2, ethanolaminephosphate cytidylyltransferase; LCFA, long-chain fatty acid; ACC1, acetyl-CoA carboxylase 1; ACLY, adenosine triphosphatecitrate lyase; FASN, fatty acid synthase; FABP, fatty acid-binding protein; SFA, saturated fatty acid; RORγt, retinoic acid-related orphan receptor gamma t; SCD1, stearoyl-CoA desaturase 1; TGF-β, transforming growth factor-beta; PI, phosphatidylinositol; Acetyl-CoA, acetyl coenzyme A.

References

1. Angela M, Endo Y, Asou HK, Yamamoto T, Tumes DJ, Tokuyama H, et al. Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells. Nat Commun 2016;7:13683.

2. O'Sullivan D, van der Windt GJ, Huang SC, Curtis JD, Chang CH, Buck MD, et al. Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 2014;41:75–88.

3. Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 2009;460:103–7.

4. Lu W, Helou YA, Shrinivas K, Liou J, Au-Yeung BB, Weiss A. The phosphatidylinositol-transfer protein Nir3 promotes PI(4,5)P2 replenishment in response to TCR signaling during T cell development and survival. Nat Immunol 2023;24:136–47.

5. Nava Lauson CB, Tiberti S, Corsetto PA, Conte F, Tyagi P, Machwirth M, et al. Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity. Cell Metab 2023;35:633–50.e9.

6. Luda KM, Longo J, Kitchen-Goosen SM, Duimstra LR, Ma EH, Watson MJ, et al. Ketolysis drives CD8+ T cell effector function through effects on histone acetylation. Immunity 2023;56:2021–35.e8.

7. Schwenk RW, Holloway GP, Luiken JJ, Bonen A, Glatz JF. Fatty acid transport across the cell membrane: regulation by fatty acid transporters. Prostaglandins Leukot Essent Fatty Acids 2010;82:149–54.

8. Zhang Y, Zhang J, Ren Y, Lu R, Yang L, Nie G. Tracing the evolution of fatty acid-binding proteins (FABPs) in organisms with a heterogeneous fat distribution. FEBS Open Bio 2020;10:861–72.

9. Field CS, Baixauli F, Kyle RL, Puleston DJ, Cameron AM, Sanin DE, et al. Mitochondrial integrity regulated by lipid metabolism is a cell-intrinsic checkpoint for treg suppressive function. Cell Metab 2020;31:422–37.e5.

10. Rodríguez-Carrio J, Alperi-López M, López P, Ballina-García FJ, Suárez A. Non-esterified fatty acids profiling in rheumatoid arthritis: associations with clinical features and Th1 response. PLoS One 2016;11:e0159573.

11. Bi X, Li F, Liu S, Jin Y, Zhang X, Yang T, et al. ω-3 polyunsaturated fatty acids ameliorate type 1 diabetes and autoimmunity. J Clin Invest 2017;127:1757–71.

12. Crow MK. Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets. Ann Rheum Dis 2023;82:999–1014.

13. Iwata S, Zhang M, Hao H, Trimova G, Hajime M, Miyazaki Y, et al. Enhanced Fatty acid synthesis leads to subset imbalance and IFN-γ overproduction in T helper 1 cells. Front Immunol 2020;11:593103.

14. Choi G, Ju HY, Bok J, Choi J, Shin JW, Oh H, et al. NRF2 is a spatiotemporal metabolic hub essential for the polyfunctionality of Th2 cells. Proc Natl Acad Sci U S A 2024;121:e2319994121.

15. Cait A, Hughes MR, Antignano F, Cait J, Dimitriu PA, Maas KR, et al. Microbiome-driven allergic lung inflammation is ameliorated by short-chain fatty acids. Mucosal Immunol 2018;11:785–95.

16. Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N, Ngom-Bru C, et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 2014;20:159–66.

17. McGeachy MJ, Cua DJ, Gaffen SL. The IL-17 family of cytokines in health and disease. Immunity 2019;50:892–906.

18. Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease. Nature 2016;535:75–84.

19. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 2010;28:445–89.

20. Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol 2015;15:545–58.

21. Cluxton D, Petrasca A, Moran B, Fletcher JM. Differential regulation of human treg and Th17 cells by fatty acid synthesis and glycolysis. Front Immunol 2019;10:115.

22. Geltink RIK, Kyle RL, Pearce EL. Unraveling the complex interplay between t cell metabolism and function. Annu Rev Immunol 2018;36:461–88.

23. Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S, Harmrolfs K, et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med 2014;20:1327–33.

24. Endo Y, Asou HK, Matsugae N, Hirahara K, Shinoda K, Tumes DJ, et al. Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase, ACC1. Cell Rep 2015;12:1042–55.

25. Young KE, Flaherty S, Woodman KM, Sharma-Walia N, Reynolds JM. Fatty acid synthase regulates the pathogenicity of Th17 cells. J Leukoc Biol 2017;102:1229–35.

26. Lee JE, Kim M, Ochiai S, Kim SH, Yeo H, Bok J, et al. Tonic type 2 immunity is a critical tissue checkpoint controlling autoimmunity in the skin. Cell Rep 2024;43:114364.

27. Wang C, Yosef N, Gaublomme J, Wu C, Lee Y, Clish CB, et al. CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell 2015;163:1413–27.

28. Furuhashi M, Hotamisligil GS. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 2008;7:489–503.

29. Yoon JH, Do JS, Velankanni P, Lee CG, Kwon HK. Gut Microbial Metabolites on Host Immune Responses in Health and Disease. Immune Netw 2023;23:e6.

30. Du HX, Yue SY, Niu D, Liu C, Zhang LG, Chen J, et al. Gut microflora modulates Th17/T_reg cell differentiation in experimental autoimmune prostatitis via the short-chain fatty acid propionate. Front Immunol 2022;13:915218.

31. Park J, Kim M, Kang SG, Jannasch AH, Cooper B, Patterson J, et al. Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway. Mucosal Immunol 2015;8:80–93.

32. Chen L, Sun M, Wu W, Yang W, Huang X, Xiao Y, et al. Microbiota metabolite butyrate differentially regulates Th1 and Th17 cells' differentiation and function in induction of colitis. Inflamm Bowel Dis 2019;25:1450–61.

33. Luu M, Pautz S, Kohl V, Singh R, Romero R, Lucas S, et al. The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes. Nat Commun 2019;10:760.

34. Haghikia A, Jörg S, Duscha A, Berg J, Manzel A, Waschbisch A, et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity 2015;43:817–29.

35. Hochrein SM, Wu H, Eckstein M, Arrigoni L, Herman JS, Schumacher F, et al. The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming. Cell Metab 2022;34:516–32.e11.

36. Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 2012;30:531–64.

37. Savage PA, Malchow S, Leventhal DS. Basic principles of tumor-associated regulatory T cell biology. Trends Immunol 2013;34:33–40.

38. Lee GR. Molecular mechanisms of T helper cell differentiation and functional specialization. Immune Netw 2023;23:e4.

39. Raud B, Roy DG, Divakaruni AS, Tarasenko TN, Franke R, Ma EH, et al. Etomoxir actions on regulatory and memory T cells are independent of cpt1a-mediated fatty acid oxidation. Cell Metab 2018;28:504–15.e7.

40. Veenbergen S, Samsom JN. Maintenance of small intestinal and colonic tolerance by IL-10-producing regulatory T cell subsets. Curr Opin Immunol 2012;24:269–76.

41. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, et al. The microbial metabolites, short-chain fatty acids, regulate colonic T_reg cell homeostasis. Science 2013;341:569–73.

42. Hao F, Tian M, Zhang X, Jin X, Jiang Y, Sun X, et al. Butyrate enhances CPT1A activity to promote fatty acid oxidation and iT_reg differentiation. Proc Natl Acad Sci U S A 2021;118:e2014681118.

43. Pompura SL, Wagner A, Kitz A, LaPerche J, Yosef N, Dominguez-Villar M, et al. Oleic acid restores suppressive defects in tissue-resident FOXP3 T_regs from patients with multiple sclerosis. J Clin Invest 2021;131:e138519.

44. Lin L, Hu M, Li Q, Du L, Lin L, Xue Y, et al. Oleic acid availability impacts thymocyte preprogramming and subsequent peripheral T_reg cell differentiation. Nat Immunol 2024;25:54–65.

45. Grajchen E, Loix M, Baeten P, Côrte-Real BF, Hamad I, Vanherle S, et al. Fatty acid desaturation by stearoyl-CoA desaturase-1 controls regulatory T cell differentiation and autoimmunity. Cell Mol Immunol 2023;20:666–79.

46. Gensous N, Charrier M, Duluc D, Contin-Bordes C, Truchetet ME, Lazaro E, et al. T follicular helper cells in autoimmune disorders. Front Immunol 2018;9:1637.

47. Kenefeck R, Wang CJ, Kapadi T, Wardzinski L, Attridge K, Clough LE, et al. Follicular helper T cell signature in type 1 diabetes. J Clin Invest 2015;125:292–303.

48. Wang J, Shan Y, Jiang Z, Feng J, Li C, Ma L, et al. High frequencies of activated B cells and T follicular helper cells are correlated with disease activity in patients with new-onset rheumatoid arthritis. Clin Exp Immunol 2013;174:212–20.

49. Feng X, Wang D, Chen J, Lu L, Hua B, Li X, et al. Inhibition of aberrant circulating Tfh cell proportions by corticosteroids in patients with systemic lupus erythematosus. PLoS One 2012;7:e51982.

50. Ryu H, Lim H, Choi G, Park YJ, Cho M, Na H, et al. Atherogenic dyslipidemia promotes autoimmune follicular helper T cell responses via IL-27. Nat Immunol 2018;19:583–93.

51. Kim J, Lee H, Lee JE, Choi G, Chung H, Kim D, et al. Liver X receptor controls follicular helper T cell differentiation via repression of TCF-1. Proc Natl Acad Sci U S A 2023;120:e2213793120.

52. Fu G, Guy CS, Chapman NM, Palacios G, Wei J, Zhou P, et al. Metabolic control of T_FH cells and humoral immunity by phosphatidylethanolamine. Nature 2021;595:724–9.

53. Son YM, Cheon IS, Goplen NP, Dent AL, Sun J. Inhibition of stearoyl-CoA desaturases suppresses follicular help T- and germinal center B- cell responses. Eur J Immunol 2020;50:1067–77.

54. Dyck L, Prendeville H, Raverdeau M, Wilk MM, Loftus RM, Douglas A, et al. Suppressive effects of the obese tumor microenvironment on CD8 T cell infiltration and effector function. J Exp Med 2022;219:e20210042.

55. Manzo T, Prentice BM, Anderson KG, Raman A, Schalck A, Codreanu GS, et al. Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells. J Exp Med 2020;217:e20191920.

56. Fan H, Xia S, Xiang J, Li Y, Ross MO, Lim SA, et al. Transvaccenic acid reprograms CD8+ T cells and anti-tumour immunity. Nature 2023;623:1034–43.

57. Amitrano AM, Kim M. Metabolic challenges in anticancer CD8 T cell functions. Immune Netw 2023;23:e9.

58. Bretscher PA. A two-step, two-signal model for the primary activation of precursor helper T cells. Proc Natl Acad Sci U S A 1999;96:185–90.

59. Raynor JL, Chi H. Nutrients: signal 4 in T cell immunity. J Exp Med 2024;221:e20221839.