bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–06–09
sixteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. NR4A1 transcriptionally regulates the differentiation of stem-like CD8+ T cells in the tumor microenvironment.
  2. Generation of CAR-TSCM: CAR-T with super clutch.
  3. Neutrophil-mediated hypoxia drives pathogenic CD8 T cell responses in cutaneous leishmaniasis.
  4. An Aggregation-Induced Emission-Based Dual Emitting Nanoprobe for Detecting Intracellular pH and Unravelling Metabolic Variations in Differentiating Lymphocytes.
  5. Tumor-associated macrophages restrict CD8+ T cell function through collagen deposition and metabolic reprogramming of the breast cancer microenvironment.
  6. Revolutionizing tumor immunotherapy: unleashing the power of progenitor exhausted T cells.
  7. miR-744-5p promotes T-cell differentiation via inhibiting STK11.
  8. The BTLA-HVEM axis restricts CAR T cell efficacy in cancer.
  9. Senescent glia link mitochondrial dysfunction and lipid accumulation.
  10. The human gut microbiome and aging.
  11. Cellular architecture shapes the naïve T cell response.
  12. Mitochondrial function of dairy calf lymphocytes from birth to immunologic maturity.
  13. De novo and salvage purine synthesis pathways across tissues and tumors.
  14. Enhancing tumor-infiltrating T cells with an exclusive fuel source.
  15. Lipid metabolism: a central modulator of RORt-mediated Th17 cell differentiation.
  16. Father's diet influences son's metabolic health through sperm RNA.
  1. Cell Rep. 2024 May 31. pii: S2211-1247(24)00629-6. [Epub ahead of print]43(6): 114301
    NR4A1 transcriptionally regulates the differentiation of stem-like CD8+ T cells in the tumor microenvironment.
    Jing Hao, Ruifeng Li, Xiaohong Zhao, Xinwei Liu, Xiang Chen, Tian Xie, Xiaoli Li, Chenjun Yao, Qinli Sun, Kun Wei, Mengting Gou, Xinxin Chi, Wei Xu, Ling Ni, Chen Dong.
      CD8+ T cells are rendered exhausted in tumor and chronic infection. Among heterogeneous exhausted T cells, a subpopulation of progenitor-like (Tpex) cells have been found important for long-term tumor or pathogen control and are also the main responders in immunotherapy. Using an RFP reporter mouse for the orphan nuclear receptor NR4A1, originally characterized as critical in T cell dysfunction, we discover that the reporter is highly expressed in Tpex cells in tumor and chronic infection. Enforced expression of Nr4a1 promotes Tpex cell accumulation, whereas tumor control is improved after Nr4a1 deletion, associated with increased effector function but decreased long-term maintenance of CD8+ T cells. Integrating chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) analysis, NR4A1 is found to bind and promote the expression of Tpex-related genes, as well as suppress terminal differentiation-associated genes. This study therefore has identified a key role of NR4A1 in Tpex regulation and provides a promising target for immunotherapy.
    Keywords:  CD8(+); CP: Cancer; CP: Immunology; NR4A1; T cell exhaustion; progenitor exhausted cell; terminally exhausted cell
    DOI:  https://doi.org/10.1016/j.celrep.2024.114301
  2. Int Immunopharmacol. 2024 Jun 03. pii: S1567-5769(24)00899-3. [Epub ahead of print]136 112379
    Generation of CAR-TSCM: CAR-T with super clutch.
    Jinhui Hu, Xiang Liu.
      CAR-T therapy has demonstrated effectiveness in hematological malignancies and is now striding into solid tumor areas. One of the main roadblocks of CAR-T therapy is T cell exhaustion normally aroused by T cell terminal differentiation due to persistent contact with antigen in vivo or in vitro manufacturing process. TSCM positions as the first, and pivotal step of naïve T cell differentiation to downstream memory and effector stages. Researchers highly seek to restrain CAR-T cells at the TSCM stage during manufacture as TSCM percentage in CAR-T products is strongly associated with better treatment response. We reviewed the recent strategies regarding CAR-TSCM generation from aspects of starting source, manufacturing process, CAR assembly, transcription factor and metabolism regulation, etc.
    Keywords:  CAR; CAR-T; CAR-T(SCM); T stem cell like memory; T(SCM)
    DOI:  https://doi.org/10.1016/j.intimp.2024.112379
  3. J Clin Invest. 2024 Jun 04. pii: e177992. [Epub ahead of print]
    Neutrophil-mediated hypoxia drives pathogenic CD8 T cell responses in cutaneous leishmaniasis.
    Erin A Fowler, Camila Farias Amorim, Klauss Mostacada, Allison Yan, Laís Amorim Sacramento, Rae A Stanco, Emily Ds Hales, Aditi Varkey, Wenjing Zong, Gary D Wu, Camila I de Oliveira, Patrick L Collins, Fernanda O Novais.
      Cutaneous leishmaniasis caused by Leishmania parasites exhibits a wide range of clinical manifestations. Although parasites influence disease severity, cytolytic CD8 T cell responses mediate disease. While these responses originate in the lymph node, we found that expression of the cytolytic effector molecule granzyme B was restricted to lesional CD8 T cells in Leishmania-infected mice, suggesting that local cues within inflamed skin induced cytolytic function. Expression of Blimp-1 (Prdm1), a transcription factor necessary for cytolytic CD8 T cell differentiation, was driven by hypoxia within the inflamed skin. Hypoxia was further enhanced by the recruitment of neutrophils that consumed oxygen to produce reactive oxygen species and ultimately increased the hypoxic state and granzyme B expression in CD8 T cells. Importantly, lesions from cutaneous leishmaniasis patients exhibited hypoxia transcription signatures that correlated with the presence of neutrophils. Thus, targeting hypoxia-driven signals that support local differentiation of cytolytic CD8 T cells may improve the prognosis for patients with cutaneous leishmaniasis, as well as other inflammatory skin diseases where cytolytic CD8 T cells contribute to pathogenesis.
    Keywords:  Hypoxia; Infectious disease; Inflammation; Neutrophils; T cells
    DOI:  https://doi.org/10.1172/JCI177992
  4. ACS Nano. 2024 Jun 04.
    An Aggregation-Induced Emission-Based Dual Emitting Nanoprobe for Detecting Intracellular pH and Unravelling Metabolic Variations in Differentiating Lymphocytes.
    Yingying Huang, Qin Zhang, Ching Ying Katherine Lam, Chuanqi Li, Chen Yang, Zhiming Zhong, Ruolin Zhang, Jiaxiang Yan, Jiareng Chen, Bohan Yin, Siu Hong Dexter Wong, Mo Yang.
      Monitoring T lymphocyte differentiation is essential for understanding T cell fate regulation and advancing adoptive T cell immunotherapy. However, current biomarker analysis methods necessitate cell lysis, leading to source depletion. Intracellular pH (pHi) can be affected by the presence of lactic acid (LA), a metabolic mediator of T cell activity such as glycolysis during T cell activation; therefore, it is a potentially a good biomarker of T cell state. In this work, a dual emitting enhancement-based nanoprobe, namely, AIEgen@F127-AptCD8, was developed to accurately detect the pHi of T cells to "read" the T cell differentiation process. The nanocore of this probe comprises a pair of AIE dyes, TPE-AMC (pH-sensitive moiety) and TPE-TCF, that form a donor-acceptor pair for sensitive detection of pHi by dual emitting enhancement analysis. The nanoprobe exhibits a distinctly sensitive narrow range of pHi values (from 6.0 to 7.4) that can precisely distinguish the differentiated lymphocytes from naïve ones based on their distinct pHi profiles. Activated CD8+ T cells demonstrate lower pHi (6.49 ± 0.09) than the naïve cells (7.26 ± 0.11); Jurkat cells exhibit lower pHi (6.43 ± 0.06) compared to that of nonactivated ones (7.29 ± 0.09) on 7 days post-activation. The glycolytic product profiles in T cells strongly correlate with their pHi profiles, ascertaining the reliability of probing pHi for predicting T cell states. The specificity and dynamic detection capabilities of this nanoprobe make it a promising tool for indirectly and noninvasively monitoring T cell activation and differentiation states.
    Keywords:  Aggregation-induced emission luminogen; Cellular metabolism; Nanoprobes; T lymphocytes; pH detection
    DOI:  https://doi.org/10.1021/acsnano.4c03796
  5. Nat Cancer. 2024 Jun 03.
    Tumor-associated macrophages restrict CD8+ T cell function through collagen deposition and metabolic reprogramming of the breast cancer microenvironment.
    Kevin M Tharp, Kelly Kersten, Ori Maller, Greg A Timblin, Connor Stashko, Fernando P Canale, Rosa E Menjivar, Mary-Kate Hayward, Ilona Berestjuk, Johanna Ten Hoeve, Bushra Samad, Alastrair J Ironside, Marina Pasca di Magliano, Alexander Muir, Roger Geiger, Alexis J Combes, Valerie M Weaver.
      Tumor progression is accompanied by fibrosis, a condition of excessive extracellular matrix accumulation, which is associated with diminished antitumor immune infiltration. Here we demonstrate that tumor-associated macrophages (TAMs) respond to the stiffened fibrotic tumor microenvironment (TME) by initiating a collagen biosynthesis program directed by transforming growth factor-β. A collateral effect of this programming is an untenable metabolic milieu for productive CD8+ T cell antitumor responses, as collagen-synthesizing macrophages consume environmental arginine, synthesize proline and secrete ornithine that compromises CD8+ T cell function in female breast cancer. Thus, a stiff and fibrotic TME may impede antitumor immunity not only by direct physical exclusion of CD8+ T cells but also through secondary effects of a mechano-metabolic programming of TAMs, which creates an inhospitable metabolic milieu for CD8+ T cells to respond to anticancer immunotherapies.
    DOI:  https://doi.org/10.1038/s43018-024-00775-4
  6. Cancer Biol Med. 2024 May 31. pii: j.issn.2095-3941.2024.0105. [Epub ahead of print]
    Revolutionizing tumor immunotherapy: unleashing the power of progenitor exhausted T cells.
    Zhang Fang, Xinyi Ding, Hao Huang, Hongwei Jiang, Jingting Jiang, Xiao Zheng.
      In exploring persistent infections and malignancies, a distinctive subgroup of CD8+ T cells, progenitor exhausted CD8+ T (Tpex) cells, has been identified. These Tpex cells are notable for their remarkable self-renewal and rapid proliferation abilities. Recent strides in immunotherapy have demonstrated that Tpex cells expand and differentiate into responsive exhausted CD8+ T cells, thus underscoring their critical role in the immunotherapeutic retort. Clinical examinations have further clarified a robust positive correlation between the proportional abundance of Tpex cells and enhanced clinical prognosis. Tpex cells have found noteworthy applications in the formulation of inventive immunotherapeutic approaches against tumors. This review describes the functions of Tpex cells in the tumor milieu, particularly their potential utility in tumor immunotherapy. Precisely directing Tpex cells may be essential to achieving successful outcomes in immunotherapy against tumors.
    Keywords:  Progenitor exhausted CD8+ T cells; TCF-1; cellular crosstalk; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2024.0105
  7. Gene. 2024 Jun 01. pii: S0378-1119(24)00516-X. [Epub ahead of print]926 148635
    miR-744-5p promotes T-cell differentiation via inhibiting STK11.
    Jiayi Han, Jianqing Huang, Jieming Hu, Wenkai Shi, Hongqiong Wang, Wenfeng Zhang, Jinquan Wang, Hongwei Shao, Han Shen, Huaben Bo, Changli Tao, Fenglin Wu.
      T cells utilized in adoptive T cell immunotherapy are typically activated in vitro. Although these cells demonstrate proliferation and anti-tumor activity following activation, they often face difficulties in sustaining long-term survival post-reinfusion. This issue is attributed to the induction of T cells into a terminal differentiation state upon activation, whereas early-stage differentiated T cells exhibit enhanced proliferation potential and survival capabilities. In previous study, we delineated four T cell subsets at varying stages of differentiation: TN, TSCM, TCM, and TEM, and acquired their miRNA expression profiles via high-throughput sequencing. In the current study, we performed a differential analysis of miRNA across these subsets, identifying a distinct miRNA, hsa-miR-744-5p, characterized by progressively increasing expression levels upon T cell activation. This miRNA is not expressed in TSCM but is notably present in TEM. Target genes of miR-744-5p were predicted, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, revealing that these genes predominantly associate with pathways related to the 'Wnt signaling pathway'. We established that miR-744-5p directly targets STK11, influencing its expression. Further, we investigated the implications of miR-744-5p on T cell differentiation and functionality. Overexpression of miR-744-5p in T cells resulted in heightened apoptosis, reduced proliferation, an increased proportion of late-stage differentiated T cells, and elevated secretion of the cytokine TNF-α. Moreover, post-overexpression of miR-744-5p led to a marked decline in the expression of early-stage differentiation-associated genes in T cells (CCR7, CD62L, LEF1, BCL2) and a significant rise in late-stage differentiation-associated genes (KLRG1, PDCD1, GZMB). In conclusion, our findings affirm that miR-744-5p contributes to the progressive differentiation of T cells by downregulating the STK11 gene expression.
    Keywords:  Progressive differentiation; T cell; microRNA
    DOI:  https://doi.org/10.1016/j.gene.2024.148635
  8. Nat Immunol. 2024 Jun;25(6): 1020-1032
    The BTLA-HVEM axis restricts CAR T cell efficacy in cancer.
    Puneeth Guruprasad, Alberto Carturan, Yunlin Zhang, Jong Hyun Cho, Kingsley Gideon Kumashie, Ruchi P Patel, Ki-Hyun Kim, Jong-Seo Lee, Yoon Lee, Jong Hoon Kim, Junho Chung, Akshita Joshi, Ivan Cohen, Maksim Shestov, Guido Ghilardi, Jaryse Harris, Raymone Pajarillo, Mathew Angelos, Yong Gu Lee, Shan Liu, Jesse Rodriguez, Michael Wang, Hatcher J Ballard, Aasha Gupta, Ositadimma H Ugwuanyi, Seok Jae Albert Hong, Audrey C Bochi-Layec, Christopher T Sauter, Linhui Chen, Luca Paruzzo, Shane Kammerman, Olga Shestova, Dongfang Liu, Laura A Vella, Stephen J Schuster, Jakub Svoboda, Patrizia Porazzi, Marco Ruella.
      The efficacy of T cell-based immunotherapies is limited by immunosuppressive pressures in the tumor microenvironment. Here we show a predominant role for the interaction between BTLA on effector T cells and HVEM (TNFRSF14) on immunosuppressive tumor microenvironment cells, namely regulatory T cells. High BTLA expression in chimeric antigen receptor (CAR) T cells correlated with poor clinical response to treatment. Therefore, we deleted BTLA in CAR T cells and show improved tumor control and persistence in models of lymphoma and solid malignancies. Mechanistically, BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2, upon trans engagement with HVEM. BTLA knockout thus promotes CAR signaling and subsequently enhances effector function. Overall, these data indicate that the BTLA-HVEM axis is a crucial immune checkpoint in CAR T cell immunotherapy and warrants the use of strategies to overcome this barrier.
    DOI:  https://doi.org/10.1038/s41590-024-01847-4
  9. Nature. 2024 Jun 05.
    Senescent glia link mitochondrial dysfunction and lipid accumulation.
    China N Byrns, Alexandra E Perlegos, Karl N Miller, Zhecheng Jin, Faith R Carranza, Palak Manchandra, Connor H Beveridge, Caitlin E Randolph, V Sai Chaluvadi, Shirley L Zhang, Ananth R Srinivasan, F C Bennett, Amita Sehgal, Peter D Adams, Gaurav Chopra, Nancy M Bonini.
      Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species1,2. Acutely, senescent cells promote wound healing3,4 and prevent tumour formation5; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy6-11, why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear12,13. Here we identify naturally occurring senescent glia in ageing Drosophila brains and decipher their origin and influence. Using Activator protein 1 (AP1) activity to screen for senescence14,15, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly lifespan and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally occurring senescent glia in vivo and indicate that these cells link key ageing phenomena: mitochondrial dysfunction and lipid accumulation.
    DOI:  https://doi.org/10.1038/s41586-024-07516-8
  10. Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2359677
    The human gut microbiome and aging.
    Evan Bradley, John Haran.
      The composition of the human gut microbiome has been observed to change over the course of an individual's life. From birth, it is shaped by mode of delivery, diet, environmental exposures, geographic location, exposures to medications, and by aging itself. Here, we present a narrative review of the gut microbiome across the lifespan with a focus on its impacts on aging and age-related diseases in humans. We will describe how it is shaped, and features of the gut microbiome that have been associated with diseases at different phases of life and how this can adversely affect healthy aging. Across the lifespan, and especially in old age, a diverse microbiome that includes organisms suspected to produce anti-inflammatory metabolites such as short-chain fatty acids, has been reported to be associated with healthy aging. These findings have been remarkably consistent across geographic regions of the world suggesting that they could be universal features of healthy aging across all cultures and genetic backgrounds. Exactly how these features of the microbiome affect biologic processes associated with aging thus promoting healthy aging will be crucial to targeting the gut microbiome for interventions that will support health and longevity.
    Keywords:  Gut microbiome; age-related disease; aging; microbiome-based theraputics
    DOI:  https://doi.org/10.1080/19490976.2024.2359677
  11. Science. 2024 Jun 07. 384(6700): eadh8697
    Cellular architecture shapes the naïve T cell response.
    Benjamin D Hale, Yannik Severin, Fabienne Graebnitz, Dominique Stark, Daniel Guignard, Julien Mena, Yasmin Festl, Sohyon Lee, Jacob Hanimann, Nathan S Zangger, Michelle Meier, David Goslings, Olga Lamprecht, Beat M Frey, Annette Oxenius, Berend Snijder.
      After antigen stimulation, naïve T cells display reproducible population-level responses, which arise from individual T cells pursuing specific differentiation trajectories. However, cell-intrinsic predeterminants controlling these single-cell decisions remain enigmatic. We found that the subcellular architectures of naïve CD8 T cells, defined by the presence (TØ) or absence (TO) of nuclear envelope invaginations, changed with maturation, activation, and differentiation. Upon T cell receptor (TCR) stimulation, naïve TØ cells displayed increased expression of the early-response gene Nr4a1, dependent upon heightened calcium entry. Subsequently, in vitro differentiation revealed that TØ cells generated effector-like cells more so compared with TO cells, which proliferated less and preferentially adopted a memory-precursor phenotype. These data suggest that cellular architecture may be a predeterminant of naïve CD8 T cell fate.
    DOI:  https://doi.org/10.1126/science.adh8967
  12. J Dairy Sci. 2024 May 31. pii: S0022-0302(24)00870-1. [Epub ahead of print]
    Mitochondrial function of dairy calf lymphocytes from birth to immunologic maturity.
    Kathryn W Kesler, Angel Abuelo.
      The inability of dairy calves to fully respond to immune stimuli until they reach maturity at 6 mo of age severely limits the use of parenteral vaccines to protect calves against disease. Immune responses are metabolically demanding, and immune cells rely on mitochondrial metabolites for their functionality. Due to the essential role of mitochondria in driving T-cell responses necessary for vaccine efficacy, we hypothesized that the mitochondrial function of dairy calf lymphocytes changes with age, from birth to immunologic maturity. In this cross-sectional study, groups of dairy calves (n = 4/group) were blood sampled at birth before colostrum intake and at 1, 2, 3, 4, 6, 8, 16, and 24 wk of age. Mid-lactation adult cows (n = 4) were also sampled to reference fully mature immune cell populations. B, CD4+, CD8+, and γδ T lymphocytes were enriched using magnetic-activated cell sorting, and their mitochondrial function was assessed with an extracellular flux analyzer. Non-mitochondrial oxygen consumption, basal respiration, maximal respiration, spare respiratory capacity, proton leak, and the oxygen consumption rate (OCR) to extracellular acidification rate (ECAR) ratio were reported. Results were compared among groups using a Kruskal-Wallis test. The OCR to ECAR ratio is an indicator of the relative proportions of oxidative phosphorylation and aerobic glycolysis which is associated with effector functions in lymphocytes. The ratio was lower in 0 wk than adults in CD4+ T-cells. For CD8+ T-cells, the OCR to ECAR ratio for the 2 wk group was lower than the 3 wk group. A lower OCR to ECAR ratio indicates more reliance on glycolytic metabolism than oxidative phosphorylation. Maximal respiration is an indication of mitochondrial efficiency and is often associated with mitochondrial mass. For γδ T-cells, the 3 wk group had higher maximal respiration than the 16 wk group, whereas for B cells maximal respiration was higher in the 1 wk compared with the 16 wk group. Basal respiration indicates all cell functions that require oxygen and was lower in the 0 wk group than the 1 wk and 3 wk groups for CD4+ T-cells. γδ T-cells exhibited lower basal respiration in the 2 wk group than the 24 wk one. Although we found minimal differences in the mitochondrial outcomes reported from non-stimulated lymphocytes from birth through 6 mo of age and mid-lactation adults who served as mature immune cell populations, these results align with previous reports from weaning aged calf and adult CD4+ T-cells. In conclusion, there was insufficient evidence to suggest that the mitochondria in the lymphocytes of dairy calves from birth through immunologic maturity had functional changes associated with age. In conclusion, the capacity of unstimulated calf mitochondria to perform oxidative phosphorylation is not associated with age.
    Keywords:  B-cells; Extracellular flux; Immunity; Immunometabolism; T-cells
    DOI:  https://doi.org/10.3168/jds.2024-24849
  13. Cell. 2024 May 30. pii: S0092-8674(24)00520-8. [Epub ahead of print]
    De novo and salvage purine synthesis pathways across tissues and tumors.
    Diem H Tran, Dohun Kim, Rushendhiran Kesavan, Harrison Brown, Trishna Dey, Mona Hoseini Soflaee, Hieu S Vu, Alpaslan Tasdogan, Jason Guo, Divya Bezwada, Houssam Al Saad, Feng Cai, Ashley Solmonson, Halie Rion, Rawand Chabatya, Salma Merchant, Nathan J Manales, Vanina T Tcheuyap, Megan Mulkey, Thomas P Mathews, James Brugarolas, Sean J Morrison, Hao Zhu, Ralph J DeBerardinis, Gerta Hoxhaj.
      Purine nucleotides are vital for RNA and DNA synthesis, signaling, metabolism, and energy homeostasis. To synthesize purines, cells use two principal routes: the de novo and salvage pathways. Traditionally, it is believed that proliferating cells predominantly rely on de novo synthesis, whereas differentiated tissues favor the salvage pathway. Unexpectedly, we find that adenine and inosine are the most effective circulating precursors for supplying purine nucleotides to tissues and tumors, while hypoxanthine is rapidly catabolized and poorly salvaged in vivo. Quantitative metabolic analysis demonstrates comparative contribution from de novo synthesis and salvage pathways in maintaining purine nucleotide pools in tumors. Notably, feeding mice nucleotides accelerates tumor growth, while inhibiting purine salvage slows down tumor progression, revealing a crucial role of the salvage pathway in tumor metabolism. These findings provide fundamental insights into how normal tissues and tumors maintain purine nucleotides and highlight the significance of purine salvage in cancer.
    Keywords:  cancer metabolism; de novo purine synthesis; in vivo isotope tracing; nucleotide diet; nucleotide metabolism; purine bases; purine degradation; purine salvage; tissue; tumor growth
    DOI:  https://doi.org/10.1016/j.cell.2024.05.011
  14. bioRxiv. 2024 May 21. pii: 2024.05.20.595053. [Epub ahead of print]
    Enhancing tumor-infiltrating T cells with an exclusive fuel source.
    Matthew L Miller, Rina Nagarajan, Timothy J Thauland, Manish J Butte.
      Solid tumors harbor immunosuppressive microenvironments that inhibit tumor infiltrating lymphocytes (TILs) through the voracious consumption of glucose. We sought to restore TIL function by providing them with an exclusive fuel source. The glucose disaccharide cellobiose, which is a building block of cellulose, contains a β-1,4-glycosidic bond that cannot be hydrolyzed by animals (or their tumors), but fungal and bacterial organisms have evolved enzymes to catabolize cellobiose and use the resulting glucose. By equipping T cells with two proteins that enable import and hydrolysis of cellobiose, we demonstrate that supplementation of cellobiose during glucose withdrawal restores T cell cytokine production and cellular proliferation. Murine tumor growth is suppressed and survival is prolonged. Offering exclusive access to a natural disaccharide is a new tool that augments cancer immunotherapies. Beyond cancer, this approach could be used to answer questions about the regulation of glucose metabolism across many cell types, biological processes, and diseases.
    DOI:  https://doi.org/10.1101/2024.05.20.595053
  15. Int Immunol. 2024 Jun 02. pii: dxae031. [Epub ahead of print]
    Lipid metabolism: a central modulator of RORt-mediated Th17 cell differentiation.
    Toshio Kanno, Keisuke Miyako, Yusuke Endo.
      Among the T helper cell subsets, Th17 cells contribute to the development of various inflammatory and autoimmune diseases, including psoriasis, rheumatoid arthritis, inflammatory bowel disease, steroid-resistant asthma, and multiple sclerosis. Retinoid-related orphan receptor gamma t (RORγt), a nuclear hormone receptor, serves as a master transcription factor for Th17 cell differentiation. Recent findings have shown that modulating the metabolic pathway is critical for Th17 cell differentiation, particularly through the engagement of de novo lipid biosynthesis. Suppression of lipid biosynthesis, either through the pharmacological inhibition or gene deletion of related enzymes in CD4+ T cells, results in significant impairment of Th17 cell differentiation. Mechanistic studies indicate that metabolic fluxes through both the fatty acid and cholesterol biosynthetic pathways have a pivotal role in the regulation of RORγt activity through the generation of endogenous RORγt lipid ligands. This review discusses recent discoveries highlighting the importance of lipid metabolism in Th17 cell differentiation and function, as well as exploring specific molecular pathways involved in RORγt activation through cellular lipid metabolism. We further elaborate on a pioneering therapeutic approach to improve inflammatory and autoimmune disorders via the inhibition of RORγt.
    Keywords:  ACC1; nuclear receptor
    DOI:  https://doi.org/10.1093/intimm/dxae031
  16. Nature. 2024 Jun 05.
    Father's diet influences son's metabolic health through sperm RNA.
    Chen Cai, Qi Chen.
      
    Keywords:  Metabolism; Non-coding RNAs; Obesity
    DOI:  https://doi.org/10.1038/d41586-024-01502-w
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