bims-imseme 2022-08-14 papers

Issue of 2022‒08‒14
eight papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

Front Immunol. 2022 ;13 946119

Metabolic regulation of T cell development.

Mengdi Zhang, Xiaoxi Lin, Zhou Yang, Xia Li, Zhiguang Zhou, Paul E Love, Jiaqi Huang, Bin Zhao.

T cell development in the thymus is tightly controlled by complex regulatory mechanisms at multiple checkpoints. Currently, many studies have focused on the transcriptional and posttranslational control of the intrathymic journey of T-cell precursors. However, over the last few years, compelling evidence has highlighted cell metabolism as a critical regulator in this process. Different thymocyte subsets are directed by distinct metabolic pathways and signaling networks to match the specific functional requirements of the stage. Here, we epitomize these metabolic alterations during the development of a T cell and review several recent works that provide insights into equilibrating metabolic quiescence and activation programs. Ultimately, understanding the interplay between cellular metabolism and T cell developmental programs may offer an opportunity to selectively regulate T cell subset functions and to provide potential novel therapeutic approaches to modulate autoimmunity.

Keywords: T cell development; T cell metabolism; thymocyte metabolism; thymocytes; thymus

DOI: https://doi.org/10.3389/fimmu.2022.946119

Front Immunol. 2022 ;13 913184

TGFβ limits Myc-dependent TCR-induced metabolic reprogramming in CD8+ T cells.

Helen Carrasco Hope, Gabriella Pickersgill, Pierpaolo Ginefra, Nicola Vannini, Graham P Cook, Robert J Salmond.

T cell activation is dependent upon the integration of antigenic, co-stimulatory and cytokine-derived signals and the availability and acquisition of nutrients from the environment. Furthermore, T cell activation is accompanied by reprogramming of cellular metabolism to provide the energy and building blocks for proliferation, differentiation and effector function. Transforming growth factor β (TGFβ) has pleiotropic effects on T cell populations, having both an essential role in the maintenance of immune tolerance but also context-dependent pro-inflammatory functions. We set out to define the mechanisms underpinning the suppressive effects of TGFβ on mouse CD8+ T cell activation. RNA-sequencing analysis of TCR-stimulated T cells determined that Myc-regulated genes were highly enriched within gene sets downregulated by TGFβ. Functional analysis demonstrated that TGFβ impeded TCR-induced upregulation of amino acid transporter expression, amino acid uptake and protein synthesis. Furthermore, TCR-induced upregulation of Myc-dependent glycolytic metabolism was substantially inhibited by TGFβ treatment with minimal effects on mitochondrial respiration. Thus, our data suggest that inhibition of Myc-dependent metabolic reprogramming represents a major mechanism underpinning the suppressive effects of TGFβ on CD8+ T cell activation.

Keywords: T cell receptor; T cells; TGFβ (transforming growth factor-beta); cytokines; metabolism; signalling

DOI: https://doi.org/10.3389/fimmu.2022.913184

Geroscience. 2022 Aug 10.

High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity.

Brenda Gonzalez, Archana Tare, Seungjin Ryu, Simon C Johnson, Gil Atzmon, Nir Barzilai, Matt Kaeberlein, Yousin Suh.

Mitochondrial dysfunction is a well-known contributor to aging and age-related diseases. The precise mechanisms through which mitochondria impact human lifespan, however, remain unclear. We hypothesize that humans with exceptional longevity harbor rare variants in nuclear-encoded mitochondrial genes (mitonuclear genes) that confer resistance against age-related mitochondrial dysfunction. Here we report an integrated functional genomics study to identify rare functional variants in ~ 660 mitonuclear candidate genes discovered by target capture sequencing analysis of 496 centenarians and 572 controls of Ashkenazi Jewish descent. We identify and prioritize longevity-associated variants, genes, and mitochondrial pathways that are enriched with rare variants. We provide functional gene variants such as those in MTOR (Y2396Lfs*29), CPS1 (T1406N), and MFN2 (G548*) as well as LRPPRC (S1378G) that is predicted to affect mitochondrial translation. Taken together, our results suggest a functional role for specific mitonuclear genes and pathways in human longevity.

Keywords: Aging; Centenarian; Genetic variant; Longevity; Mitochondria

DOI: https://doi.org/10.1007/s11357-022-00634-z

Front Immunol. 2022 ;13 911050

Yuling Chen, Yuanchun Ye, Pierre-Louis Krauß, Pelle Löwe, Moritz Pfeiffenberger, Alexandra Damerau, Lisa Ehlers, Thomas Buttgereit, Paula Hoff, Frank Buttgereit, Timo Gaber.

Cellular metabolism modulates effector functions in human CD4+ T (Th) cells by providing energy and building blocks. Conversely, cellular metabolic responses are modulated by various influences, e.g., age. Thus, we hypothesized that metabolic reprogramming in human Th cells during aging modulates effector functions and contributes to "inflammaging", an aging-related, chronic, sterile, low-grade inflammatory state characterized by specific proinflammatory cytokines. Analyzing the metabolic response of human naive and memory Th cells from young and aged individuals, we observed that memory Th cells exhibit higher glycolytic and mitochondrial fluxes than naive Th cells. In contrast, the metabolism of the latter was not affected by donor age. Memory Th cells from aged donors showed a higher respiratory capacity, mitochondrial content, and intracellular ROS production than those from young donors without altering glucose uptake and cellular ATP levels, which finally resulted in higher secreted amounts of proinflammatory cytokines, e.g., IFN-γ, IP-10 from memory Th cells taken from aged donors after TCR-stimulation which were sensitive to ROS inhibition. These findings suggest that metabolic reprogramming in human memory Th cells during aging results in an increased expression of proinflammatory cytokines through enhanced ROS production, which may contribute to the pathogenesis of inflammaging.

Keywords: ROS; aging; cytokines; memory Th cells; metabolism; proliferation

DOI: https://doi.org/10.3389/fimmu.2022.911050

World J Gastrointest Oncol. 2022 Jun 15. 14(6): 1124-1140

Glutamine deprivation impairs function of infiltrating CD8+ T cells in hepatocellular carcinoma by inducing mitochondrial damage and apoptosis.

Wei Wang, Meng-Nan Guo, Ning Li, De-Quan Pang, Jing-Hua Wu.

BACKGROUND: The functions of infiltrating CD8+ T cells are often impaired due to tumor cells causing nutrient deprivation in the tumor microenvironment. Thus, the mechanisms of CD8+ T cell dysfunction have become a hot research topic, and there is increased interest on how changes in metabolomics correlate with CD8+ T cell dysfunction.AIM: To investigate whether and how glutamine metabolism affects the function of infiltrating CD8+ T cells in hepatocellular carcinoma.
METHODS: Immunohistochemical staining and immunofluorescence were performed on surgically resected liver tissues from patients. Differentially expressed genes in infiltrating CD8+ T cells in hepatocellular carcinoma were detected using RNA sequencing. Activated CD8+ T cells were co-cultured with Huh-7 cells for 3 d. The function and mitochondrial status of CD8+ T cells were analyzed by flow cytometry, quantitative real-time polymerase chain reaction, and transmission electron microscopy. Next, CD8+ T cells were treated with the mitochondrial protective and damaging agents. Functional alterations in CD8+ T cells were detected by flow cytometry. Then, complete medium without glutamine was used to culture cells and their functional changes and mitochondrial status were detected.
RESULTS: There were a large number of infiltrating PD-1+CD8+ T cells in liver cancer tissues. Next, we co-cultured CD8+ T cells and Huh-7 cells to explore the regulatory effect of hepatoma cells on CD8+ T cells. Flow cytometry results revealed increased PD-1 expression and decreased secretion of perforin (PRF1) and granzyme B (GZMB) by CD8+ T cells in the co-culture group. Meanwhile, JC-1 staining was decreased and the levels of reactive oxygen species and apoptosis were increased in CD8+ T cells of the co-culture group; additionally, the mitochondria of these cells were swollen. When CD8+ T cells were treated with the mitochondrial protective and damaging agents, their function was restored and inhibited, respectively, through the mitochondrial damage and apoptotic pathways. Subsequently, complete medium without glutamine was used to culture cells. As expected, CD8+ T cells showed functional downregulation, mitochondrial damage, and apoptosis.
CONCLUSION: Glutamine deprivation impairs the function of infiltrating CD8+ T cells in hepatocellular carcinoma through the mitochondrial damage and apoptotic pathways.

Keywords: CD8+ T cells; Glutamine; Hepatocellular carcinoma; Mitochondrial damage; T cell function

DOI: https://doi.org/10.4251/wjgo.v14.i6.1124

Int J Mol Sci. 2022 Jul 27. pii: 8272. [Epub ahead of print]23(15):

Regulation of CD4+ and CD8+ T Cell Biology by Short-Chain Fatty Acids and Its Relevance for Autoimmune Pathology.

Carmen Schiweck, Sharmili Edwin Thanarajah, Mareike Aichholzer, Silke Matura, Andreas Reif, Elske Vrieze, Andreas Weigert, Alexander Visekruna.

The gut microbiota encodes a broad range of enzymes capable of synthetizing various metabolites, some of which are still uncharacterized. One well-known class of microbiota-derived metabolites are the short-chain fatty acids (SCFAs) such as acetate, propionate, butyrate and valerate. SCFAs have long been considered a mere waste product of bacterial metabolism. Novel results have challenged this long-held dogma, revealing a central role for microbe-derived SCFAs in gut microbiota-host interaction. SCFAs are bacterial signaling molecules that act directly on host T lymphocytes by reprogramming their metabolic activity and epigenetic status. They have an essential biological role in promoting differentiation of (intestinal) regulatory T cells and in production of the anti-inflammatory cytokine interleukin-10 (IL-10). These small molecules can also reach the circulation and modulate immune cell function in remote tissues. In experimental models of autoimmune and inflammatory diseases, such as inflammatory bowel disease, multiple sclerosis or diabetes, a strong therapeutic potential of SCFAs through the modulation of effector T cell function was observed. In this review, we discuss current research activities toward understanding a relevance of microbial SCFA for treating autoimmune and inflammatory pathologies from in vitro to human studies.

Keywords: RCT; T cell; immune system; intervention; short chain fatty acid

DOI: https://doi.org/10.3390/ijms23158272