T lymphocytes (also named T cells) are the main components of lymphocytes, which derived from bone marrow pluripotent stem cells. Immunotherapy based on T cells has been confirmed as a successful method for the treatment of various diseases (1–3). The differentiation, longevity, durability, and functionality of T cells play vital roles in regulating the efficacy of immunotherapy, which are largely determined by the metabolic activity of glucose, lipid and amino acid (4, 5). Clarifying the metabolic status in T cells can help to control T cell differentiation and fate, so that the effect of immunotherapy based on T cells can be amplified.

Lipids, consisting of acylglycerols, isoprenoids, sterols, and phospholipids, etc., are hydrophobic biomolecules making up biological membranes (6, 7). Besides participating in energy metabolism, lipids on the membranes can also give rise to signaling transduction in response to extracellular stimuli through working as second messengers, highlighting the importance of lipid components on membrane (8, 9). As signaling molecules, lipid metabolism in cells, including biosynthesis, storage and degradation, participates in controlling the status and function of various cells, including T cells. Actually, the correlation between lipid metabolism and T cells has received limited but increasing concern since related publication firstly reported in 1985 (9). Till now, the effect and status of lipid metabolism has been partly revealed in regulating the differentiation, longevity and activity of T cells. For instance, Pearce et al. (10) has demonstrated that the deficiency of mitochondrial long chain fatty acid oxidation (LC-FAO) caused by specific deletion of TNF receptor associated factor 6 (TRAF6) in T cells results in defect in their ability to generate long lived memory T (T_M) cells, highlighting that LC-FAO is indispensable to the formation of T_M cells. Opposite results indicated that LC-FAO is not required for T_M cell formation in both human and mice (11). These contradictory results suggested the complicated and vital effect of lipid metabolism in T cells. However, limited studies have been published in this field, which means that researches on lipid metabolism in T cells is still in development stage. Analyzing what has been achieved in this field can help us to estimate the developmental trend in lipid metabolism in T cells and guide experimentation strategies and funding decisions.

Bibliometrics is a method exploring library and information science through comprehensively analyzing the bibliographic material based on quantitative measurement (12). Bibliometrics can help researchers quickly grasp the hotspots and development trends in their fields, laying a cornerstone for the direction of future researched (13, 14). Over the years, the outcomes of application of bibliometrics in immune cells are fruitful (15–17). However, bibliometric study on the relationship between T cells and lipid metabolism is still a void. Therefore, we here performed a bibliometrics study on lipid metabolism in T cells based on data published to help to make further decisions in this field.

In this study, we analyzed the main knowledge domain and emerging trends of lipid metabolism in T cells. Increasing annual outputs and citations of publication were found with time. The USA was the most productive country among the 32 countries, and nine of the top 12 productivity institutions are located in the USA. Among the authors work in the institutions in the USA, Chi H was the most representative. His team mainly concentrated on the effect of lipid metabolism on the differentiation and maintenance of T follicular helper (T-FH) and tregs (72, 73, 75, 78). Their latest study on T-FH cells revealed cytidine diphosphate (CDP)-ethanolamine pathway, along with C-X-C motif chemokine receptor 5 (CXCR5) as essential factors for T-FH cell differentiation (72). Besides, they found that inhibiting SREBPs-depended lipid synthesis in tregs can unleash effective and safe antitumour immune responses, highlighting the potential of SREBPs as checkpoints for tregs (78). Among the top 12 productive institutions, the most cited institution is the Duke University in the USA (published 5 articles, cited 1574 times). The most cited publication in the Duke University is written in 2011 by Rathmell JC who found that CD4⁺ T cell subsets require distinct metabolic programs (77). In detail, they reported that Th1, Th2, and Th17 cells are highly glycolytic due to the highly expressed glucose transporter glucose transporter 1 (Glut1) on the membrane, while low expressive level of Glut1 but high lipid oxidation rates are detected in tregs.

According to the published documents, lipid metabolism regulates the fate of both CD4⁺ and CD8⁺ T cells ( Table 7 , Figure 7 ). Based on the timelines of references and keywords, and burst of keywords, the differentiation of CD4⁺ T cells, especially tregs, draw large attention recently. Th17 cells are characterized by the secretion of pro-inflammatory cytokine IL-17 to induce inflammatory diseases and tumors, and its differentiation is positively controlled by the nuclear receptor retinoic acid receptor-related orphan receptor γ (RORγt) (41, 42). Accumulation of the cholesterol precursor desmosterol can specifically activate RORγt and subsequently trigger Th17 differentiation (27). Similarly, 7β, 27-dihydroxycholesterol, a derivative oxysterol of cholesterol, was identified as the most selective and potent agonist for RORγt, which can restore the inhibitory effect of ursolic acid (an RORγt inhibitor) on Th17 differentiation (29). In summary, cholesterol uptake and biosynthesis programs are enhanced, whereas cholesterol efflux and metabolism programs are inhibited during Th17 differentiation. Similar effect of cholesterol on tregs differentiation has also been confirmed, and liver kinase B1 (LKB1) was identified as a key regulator. Researchers have proved the mevalonate pathway (the first step of cholesterol synthesis) as the most affected pathway in tregs with specific mTOR deletion (75). Also, tregs with LKB1-deficient showed impaired suppressive activity, which can be restored by the enhancement of the mevalonate pathway (43). Besides, it has been shown that geranylgeranyl pyrophosphate (GGPP), an intermediate metabolites of cholesterol synthesis, amplifies Tregs differentiation via enhancing signal transducer and activator of transcription 5 (STAT5) phosphorylation in colitis (24). However, there exists opposite evidence demonstrating a conversed effect of the cholesterol biosynthesis pathway (CBP) on tregs. Researchers showed that targeting SREBPs, a key regulator of cholesterol synthesis, in tregs can unleash its effective anti-tumour responses without autoimmune toxicity (78). The function of other lipids on CD4⁺ T cells has also been studied previously. For instance, naive CD4⁺ T cells with depletion of acid sphingomyelinase (ASM), which is a phospholipids hydrolase enzyme, possess a greater probability to differentiate into Th1 and Th17 cells which can facilitate anti-tumor immunity in non-small-cell lung cancer (31). Besides, Michalek RD et al. (77) revealed that lipid oxidation based activation of AMP-activated protein kinase is required for the generation of Tregs. However, Raud et al. (11) and Saravia et al. (44) argued that fatty acid oxidation medicated by carnitine palmitoyltransferase 1A (CPT1A) is not indispensable to tregs generation or function in vivo. Although dispute exists in the effect of lipids on tregs, the importance of them in CD4⁺ T cells differentiation should be attached.

In addition to CD4⁺ T cells, lipids are also indispensable to CD8⁺ T cells. Cai et al. (45) indicated that activation of RAR related orphan receptor A (RORɑ) with SR1078 (a cholesterol synthetic agonist) can impair the survival and proliferation of activated CD8⁺ T cells. Besides, ablation of cytochrome P450 family 27 subfamily A member 1 (CYP27A1), a rate-limiting enzyme responsible for 27-hydroxycholesterol biosynthesis, could dramatically inhibit metastasis of cancers by decreasing the amount of CD8⁺ T cells (30). These results indicated a positive cholesterol content in CD8⁺ T cells enhances their effect. However, excessive cholesterol in tumor microenvironment was proved to be an inhibitor regulating the anti-tumor activity of CD8⁺ T cells (46). The role of other lipids on CD8⁺ T cells has also been explored previously. For instance, Corrado et al. (39) found that deficiency of cardiolipin-synthesizing enzyme PTPMT1 results in poor response of CD8⁺ T cells to antigens due to the lack of essential cardiolipin. Additionally, Pearce et al. (10) has indicated that the deficiency of long chain fatty acid oxidation (LC-FAO) in T cells leads to defect in their ability to generate long lived memory T (TM) cells, However, Raud et al. (11) demonstrated that LC-FAO is not required for TM cells formation in vivo. Besides, Pan et al. (47) reported that specific deficiency of fatty-acid-binding proteins 4 and 5 (FABP4 and FABP5) hampers exogenous free fatty acid uptake by mouse CD8⁺ tissue-resident Tm cells and reduces their survival, while having no effect on the survival of central Tm cells in lymph nodes.

In light of the effect of lipid metabolism on T cells, clearing drugs or inhibitors targeting key enzymes regulating lipid metabolism seems to be helpful ( Table 8 , Figure 7 ). Among these drugs, the cholesterol-lowering chemicals Statin, an inhibitor of HMGCR, is the most widely used. The most recognized role of statin is to promote the differentiation of CD4⁺ T cells into Th2, whereas to inhibit that into Th1 and Th17 in inflammation or autoimmune diseases (49–54). However, Shimada et al. (48) identified statin as a drug inducing Th1 in patients with acute coronary syndrome. As for tregs, the effect of statins is also in dispute. Studies have reported that tregs proliferation, activation and immunological suppressive ability are largely restricted in the presence of simvastatin (75). Opposing data were available regarding the role of statins in patients with rheumatoid arthritis or acute coronary syndrome in which increased number of tregs were detected after treatment with statins (55, 56). For CD8⁺ T cells, statins have been clarified to attenuate T cells exhaustion in subjects with HIV-1 infection (57) and minimize the incidence of tumor recurrence of breast cancer (58). Above evidence suggest the potential value of statins in inflammation, autoimmune diseases and tumors. However, most studies published now are mainly on statins, and statins may elevate the amount and activity of tregs in some patients, which may lead to a terrible outcome for some patients with cancers. Understanding the reason why some effective therapies targeting lipid metabolism function in some patients but not in others, mining new drugs targeting other key enzymes, and exploiting the combined use of drugs targeting lipid metabolism with immunotherapy, radiotherapy or chemotherapy are our future research direction.

Although we summarized the past and looked to the trends in further in the field of lipid metabolism in T cells through a relatively comprehensive bibliometrics analysis, there still exist several limitations. First, despite our efforts to obtain the most comprehensive literature, some articles were still not included in the analysis, which may cause bias in the analysis. Second, some of the studies with excellent quality published in recent years may failed to obtain excessive citations due to the limited time span, they had not been highlighted in this analysis. Thirdly, this project is performed based on machine algorithm, which may lead to a slightly insufficient evidence.

Our results indicated that researches on lipid metabolism in T cells are developing rapidly at present. The USA is a major producing country, which generates many breakthroughs in this field. Frontiers in Immunology and Nature were the most prolific and cited journals, respectively. Finally, the correlation between lipid metabolism and Th17 and Tregs cells attracted increasing attention recently.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

PC, CZ, and SJ performed this bibliomrtrics analysis and wrote manuscript. YZ, YL, QX, and JC participated in experimental design and manuscript writing. HL and XF designed this study and organized the manuscript writing. All authors contributed to the article and approved the submitted version.

This work was supported by the National Key Research and Development Program (grant number 2016YFC0906400) and China’s National Natural Science Foundation (grant number 81874059).

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.

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