T Cell Activation: The importance of methionine metabolism
The immune system relies on a number of different cells types that work together to detect and clear unwanted infections from the body. T helper cells (also known as CD4+ T cells, and hereafter referred to as T cells) play an important role in this process as they modulate the activity of the immune cells that rid the body of infections. Antigens on the surface of infected cells can activate different subpopulations of T cells by binding to antigen-specific receptors on the surface of the T cells (Figure 1). Once activated, the T cells proliferate rapidly and work together to mediate the immune response against the antigen.
This rapid expansion of T cells is, however, metabolically taxing because DNA, proteins and other biomolecules have to be produced prior to every division of the cells. The synthesis of new proteins during this period relies on the T cells importing the essential amino acid methionine. In addition to its role in protein synthesis, methionine can also enter the 'methionine cycle' and be converted into s-adenosylmethionine (SAM), which provides methyl groups for numerous biochemical reactions.
SAM is a substrate for methyltransferase enzymes that are involved in the methylation of many different molecules (see Figure 1). The addition of a methyl group to a histone protein, for example, can alter gene transcription (Allis and Jenuwein, 2016); the methylation of other proteins influences processes such as signal transduction and metabolism (Murn and Shi, 2017); and the methylation of RNA can have a significant influence on gene expression (Zhao et al., 2017). Now, in eLife, Linda Sinclair and Doreen Cantrell, both at the University of Dundee, and co-workers at Dundee, Vanderbilt University and Duke University report that in addition to importing methionine for protein synthesis, activated T cells use it to generate the methyl groups needed for the methylation of DNA and RNA – processes that drive the differentiation and proliferation of T cells (Sinclair et al., 2019).
Using high-resolution mass spectrometry and metabolic labeling, Sinclair et al. showed that the activation of T cells by antigens led to a rapid upregulation of a methionine transporter called Slc7a5. The antigen activation of T cells also led to a marked increase in methyltransferases: however, the ability of these enzymes to methylate DNA, RNA or a protein depends on the availability of SAM. Since the expression of the enzymes that control the level of SAM do not change as a result of T cell activation, Sinclair et al. conclude that the import of methionine through Slc7a5 is the rate-limiting factor for the generation of methyl groups during T cell activation.
The expression of receptors for IL2 – a growth factor that drives proliferation of T cells – is also increased in response to antigen engagement with T cell receptors. Sinclair et al. observed that IL2 receptors were still upregulated even in the absence of methionine or the methionine transporter. This suggests that activation signals prepare cells to utilize extracellular methionine, but that the rapid upregulation of Slc7a5 and import of methionine is needed for the full activation of T cells.
Previous studies have shown that two other proteins – the protein kinase mTOR, which is involved ribosome biogenesis, protein translation and a number of other processes (Sabatini, 2017); and the transcription factor Myc – have important roles in regulating metabolism in T cells (Powell et al., 2012; MacIver et al., 2013), as does the upregulation of the nutrient transporters that import key metabolic building blocks such as glutamine and leucine. The fact that the activation of mTOR also enhances the expression of Myc and an amino acid transporter called CD98 illustrates the close connections between metabolic reprogramming and amino acid availability in immune cells (Wang et al., 2011; Sinclair et al., 2013). Sinclair et al. also showed that mTOR is partially dependent on the import of methionine to drive protein synthesis and fully activate the T cells.
It was also know that Slc7a5 imports leucine (in addition to importing methionine), and that the absence of either of these amino acids in the T cell leads to suboptimal activation of mTOR. It is possible that the need for multiple metabolites to support differentiation and proliferation may be a way of preventing T cells being activated when they should not be. Given recent advances in single-cell analysis it is conceivable that researchers might one day be able to measure changes in the epigenome (and also the transcriptome, proteome, acetylome and methylome) of T cells and combine these results with measurements of the flux through metabolic pathways to better understand the dynamic changes in T cells that underlie immune function. While aspects of the study by Sinclair et al. highlight the complexity of the metabolic reprogramming that T cells undergo during activation and differentiation, it also moves the field forward by establishing how the essential amino acid methionine supports T cell function. Precisely how levels of dietary methionine will contribute to methionine uptake by T cells – and whether those levels are modulated during infection, cancer or autoimmunity to influence T cell responses – is not yet known and will require further study.
References
-
The molecular hallmarks of epigenetic controlNature Reviews Genetics 17:487–500.https://doi.org/10.1038/nrg.2016.59
-
Metabolic regulation of T lymphocytesAnnual Review of Immunology 31:259–283.https://doi.org/10.1146/annurev-immunol-032712-095956
-
The winding path of protein methylation research: milestones and new frontiersNature Reviews Molecular Cell Biology 18:517–527.https://doi.org/10.1038/nrm.2017.35
-
Regulation of immune responses by mTORAnnual Review of Immunology 30:39–68.https://doi.org/10.1146/annurev-immunol-020711-075024
-
Post-transcriptional gene regulation by mRNA modificationsNature Reviews Molecular Cell Biology 18:31–42.https://doi.org/10.1038/nrm.2016.132
Article and author information
Author details
Publication history
- Version of Record published: May 2, 2019 (version 1)
Copyright
© 2019, Klein Geltink and Pearce
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 4,922
- views
-
- 572
- downloads
-
- 26
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Immunology and Inflammation
Environmental air irritants including nanosized carbon black (nCB) can drive systemic inflammation, promoting chronic obstructive pulmonary disease (COPD) and emphysema development. The let-7 microRNA (Mirlet7 miRNA) family is associated with IL-17-driven T cell inflammation, a canonical signature of lung inflammation. Recent evidence suggests the Mirlet7 family is downregulated in patients with COPD, however, whether this repression conveys a functional consequence on emphysema pathology has not been elucidated. Here, we show that overall expression of the Mirlet7 clusters, Mirlet7b/Mirlet7c2 and Mirlet7a1/Mirlet7f1/Mirlet7d, are reduced in the lungs and T cells of smokers with emphysema as well as in mice with cigarette smoke (CS)- or nCB-elicited emphysema. We demonstrate that loss of the Mirlet7b/Mirlet7c2 cluster in T cells predisposed mice to exaggerated CS- or nCB-elicited emphysema. Furthermore, ablation of the Mirlet7b/Mirlet7c2 cluster enhanced CD8+IL17a+ T cells (Tc17) formation in emphysema development in mice. Additionally, transgenic mice overexpressing Mirlet7g in T cells are resistant to Tc17 and CD4+IL17a+ T cells (Th17) development when exposed to nCB. Mechanistically, our findings reveal the master regulator of Tc17/Th17 differentiation, RAR-related orphan receptor gamma t (RORγt), as a direct target of Mirlet7 in T cells. Overall, our findings shed light on the Mirlet7/RORγt axis with Mirlet7 acting as a molecular brake in the generation of Tc17 cells and suggest a novel therapeutic approach for tempering the augmented IL-17-mediated response in emphysema.
-
- Immunology and Inflammation
SARS-CoV-2 vaccines have been used worldwide to combat COVID-19 pandemic. To elucidate the factors that determine the longevity of spike (S)-specific antibodies, we traced the characteristics of S-specific T cell clonotypes together with their epitopes and anti-S antibody titers before and after BNT162b2 vaccination over time. T cell receptor (TCR) αβ sequences and mRNA expression of the S-responded T cells were investigated using single-cell TCR- and RNA-sequencing. Highly expanded 199 TCR clonotypes upon stimulation with S peptide pools were reconstituted into a reporter T cell line for the determination of epitopes and restricting HLAs. Among them, we could determine 78 S epitopes, most of which were conserved in variants of concern (VOCs). After the 2nd vaccination, T cell clonotypes highly responsive to recall S stimulation were polarized to follicular helper T (Tfh)-like cells in donors exhibiting sustained anti-S antibody titers (designated as ‘sustainers’), but not in ‘decliners’. Even before vaccination, S-reactive CD4+ T cell clonotypes did exist, most of which cross-reacted with environmental or symbiotic microbes. However, these clonotypes contracted after vaccination. Conversely, S-reactive clonotypes dominated after vaccination were undetectable in pre-vaccinated T cell pool, suggesting that highly responding S-reactive T cells were established by vaccination from rare clonotypes. These results suggest that de novo acquisition of memory Tfh-like cells upon vaccination may contribute to the longevity of anti-S antibody titers.