bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023‒11‒12
fifteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. 13C tracer analysis reveals the landscape of metabolic checkpoints in human CD8+ T cell differentiation and exhaustion.
  2. Maladaptive T-Cell Metabolic Fitness in Autoimmune Diseases.
  3. Transcriptional and epigenetic regulators of human CD8+ T cell function identified through orthogonal CRISPR screens.
  4. Amino acid metabolism reprogramming: shedding new light on T cell anti-tumor immunity.
  5. NMDAR-directed CAAR T cells show promise for autoimmune encephalitis.
  6. The dysfunctional immune response in renal cell carcinoma correlates with changes in the metabolic landscape of ccRCC during disease progression.
  7. Engineering metabolism to modulate immunity.
  8. SIKs Regulate HDAC7 Stabilization and Cytokine Recall in Late-Stage T Cell Effector Differentiation.
  9. From aging to long COVID: exploring the convergence of immunosenescence, inflammaging, and autoimmunity.
  10. Transposable Element Signatures Define Stages of T-cell Exhaustion.
  11. c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8+ T cell immunity.
  12. Immune cells are associated with mortality: the Health and Retirement Study.
  13. SUV39H1 Ablation Enhances Long-Term CAR-T Function in Solid Tumors.
  14. Gut microbiota-mediated IL-22 alleviates metabolic inflammation.
  15. Zfp281 and Zfp148 control CD4+ T cell thymic development and TH2 functions.
  1. Front Immunol. 2023 ;14 1267816
    13C tracer analysis reveals the landscape of metabolic checkpoints in human CD8+ T cell differentiation and exhaustion.
    Alexander Kirchmair, Niloofar Nemati, Giorgia Lamberti, Marcel Trefny, Anne Krogsdam, Anita Siller, Paul Hörtnagl, Petra Schumacher, Sieghart Sopper, Adolf Sandbichler, Alfred Zippelius, Bart Ghesquière, Zlatko Trajanoski.
      Introduction: Naïve T cells remain in an actively maintained state of quiescence until activation by antigenic signals, upon which they start to proliferate and generate effector cells to initiate a functional immune response. Metabolic reprogramming is essential to meet the biosynthetic demands of the differentiation process, and failure to do so can promote the development of hypofunctional exhausted T cells.Methods: Here we used 13C metabolomics and transcriptomics to study the metabolism of CD8+ T cells in their complete course of differentiation from naïve over stem-like memory to effector cells and in exhaustion-inducing conditions.
    Results: The quiescence of naïve T cells was evident in a profound suppression of glucose oxidation and a decreased expression of ENO1, downstream of which no glycolytic flux was detectable. Moreover, TCA cycle activity was low in naïve T cells and associated with a downregulation of SDH subunits. Upon stimulation and exit from quiescence, the initiation of cell growth and proliferation was accompanied by differential expression of metabolic enzymes and metabolic reprogramming towards aerobic glycolysis with high rates of nutrient uptake, respiration and lactate production. High flux in anabolic pathways imposed a strain on NADH homeostasis, which coincided with engagement of the proline cycle for mitochondrial redox shuttling. With acquisition of effector functions, cells increasingly relied on glycolysis as opposed to oxidative phosphorylation, which was, however, not linked to changes in mitochondrial abundance. In exhaustion, decreased effector function concurred with a reduction in mitochondrial metabolism, glycolysis and amino acid import, and an upregulation of quiescence-associated genes, TXNIP and KLF2, and the T cell suppressive metabolites succinate and itaconate.
    Discussion: Overall, these results identify multiple metabolic features that regulate quiescence, proliferation and effector function, but also exhaustion of CD8+ T cells during differentiation. Thus, targeting these metabolic checkpoints may be a promising therapeutic strategy for both prevention of exhaustion and promotion of stemness of anti-tumor T cells.
    Keywords:  13C tracer analysis; RNA sequencing; differentiation; exhaustion; immunometabolism; stem cell memory cells
    DOI:  https://doi.org/10.3389/fimmu.2023.1267816
  2. Cells. 2023 Oct 29. pii: 2541. [Epub ahead of print]12(21):
    Maladaptive T-Cell Metabolic Fitness in Autoimmune Diseases.
    Irene Rose Antony, Brandon Han Siang Wong, Dermot Kelleher, Navin Kumar Verma.
      Immune surveillance and adaptive immune responses, involving continuously circulating and tissue-resident T-lymphocytes, provide host defense against infectious agents and possible malignant transformation while avoiding autoimmune tissue damage. Activation, migration, and deployment of T-cells to affected tissue sites are crucial for mounting an adaptive immune response. An effective adaptive immune defense depends on the ability of T-cells to dynamically reprogram their metabolic requirements in response to environmental cues. Inability of the T-cells to adapt to specific metabolic demands may skew cells to become either hyporesponsive (creating immunocompromised conditions) or hyperactive (causing autoimmune tissue destruction). Here, we review maladaptive T-cell metabolic fitness that can cause autoimmune diseases and discuss how T-cell metabolic programs can potentially be modulated to achieve therapeutic benefits.
    Keywords:  LFA-1; T-cell function; T-cell motility; autoimmunity; glycolysis; metabolites; psoriasis; rheumatoid arthritis
    DOI:  https://doi.org/10.3390/cells12212541
  3. Nat Genet. 2023 Nov 09.
    Transcriptional and epigenetic regulators of human CD8+ T cell function identified through orthogonal CRISPR screens.
    Sean R McCutcheon, Adam M Swartz, Michael C Brown, Alejandro Barrera, Christian McRoberts Amador, Keith Siklenka, Lucas Humayun, Maria A Ter Weele, James M Isaacs, Timothy E Reddy, Andrew S Allen, Smita K Nair, Scott J Antonia, Charles A Gersbach.
      Clinical response to adoptive T cell therapies is associated with the transcriptional and epigenetic state of the cell product. Thus, discovery of regulators of T cell gene networks and their corresponding phenotypes has potential to improve T cell therapies. Here we developed pooled, epigenetic CRISPR screening approaches to systematically profile the effects of activating or repressing 120 transcriptional and epigenetic regulators on human CD8+ T cell state. We found that BATF3 overexpression promoted specific features of memory T cells and attenuated gene programs associated with cytotoxicity, regulatory T cell function, and exhaustion. Upon chronic antigen stimulation, BATF3 overexpression countered phenotypic and epigenetic signatures of T cell exhaustion. Moreover, BATF3 enhanced the potency of CAR T cells in both in vitro and in vivo tumor models and programmed a transcriptional profile that correlates with positive clinical response to adoptive T cell therapy. Finally, we performed CRISPR knockout screens that defined cofactors and downstream mediators of the BATF3 gene network.
    DOI:  https://doi.org/10.1038/s41588-023-01554-0
  4. J Exp Clin Cancer Res. 2023 Nov 03. 42(1): 291
    Amino acid metabolism reprogramming: shedding new light on T cell anti-tumor immunity.
    Yue Zheng, Yiran Yao, Tongxin Ge, Shengfang Ge, Renbing Jia, Xin Song, Ai Zhuang.
      Metabolic reprogramming of amino acids has been increasingly recognized to initiate and fuel tumorigenesis and survival. Therefore, there is emerging interest in the application of amino acid metabolic strategies in antitumor therapy. Tremendous efforts have been made to develop amino acid metabolic node interventions such as amino acid antagonists and targeting amino acid transporters, key enzymes of amino acid metabolism, and common downstream pathways of amino acid metabolism. In addition to playing an essential role in sustaining tumor growth, new technologies and studies has revealed amino acid metabolic reprograming to have wide implications in the regulation of antitumor immune responses. Specifically, extensive crosstalk between amino acid metabolism and T cell immunity has been reported. Tumor cells can inhibit T cell immunity by depleting amino acids in the microenvironment through nutrient competition, and toxic metabolites of amino acids can also inhibit T cell function. In addition, amino acids can interfere with T cells by regulating glucose and lipid metabolism. This crucial crosstalk inspires the exploitation of novel strategies of immunotherapy enhancement and combination, owing to the unprecedented benefits of immunotherapy and the limited population it can benefit. Herein, we review recent findings related to the crosstalk between amino acid metabolism and T cell immunity. We also describe possible approaches to intervene in amino acid metabolic pathways by targeting various signaling nodes. Novel efforts to combine with and unleash potential immunotherapy are also discussed. Hopefully, some strategies that take the lead in the pipeline may soon be used for the common good.
    Keywords:  Amino acid; Immunotherapy; Metabolism reprogramming; T cell; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13046-023-02845-4
  5. Nat Rev Immunol. 2023 Nov 08.
    NMDAR-directed CAAR T cells show promise for autoimmune encephalitis.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-023-00969-4
  6. Cancer Immunol Immunother. 2023 Nov 08.
    The dysfunctional immune response in renal cell carcinoma correlates with changes in the metabolic landscape of ccRCC during disease progression.
    Nicola E Annels, M Denyer, D Nicol, S Hazell, A Silvanto, M Crockett, M Hussain, Carla Moller-Levet, Hardev Pandha.
      Renal cell carcinoma is an immunogenic tumour with a prominent dysfunctional immune cell infiltrate, unable to control tumour growth. Although tyrosine kinase inhibitors and immunotherapy have improved the outlook for some patients, many individuals are non-responders or relapse despite treatment. The hostile metabolic environment in RCC affects the ability of T-cells to maintain their own metabolic programme constraining T-cell immunity in RCC. We investigated the phenotype, function and metabolic capability of RCC TILs correlating this with clinicopathological features of the tumour and metabolic environment at the different disease stages. Flow cytometric analysis of freshly isolated TILs showed the emergence of exhausted T-cells in advanced disease based on their PD-1high and CD39 expression and reduced production of inflammatory cytokines upon in vitro stimulation. Exhausted T-cells from advanced stage disease also displayed an overall phenotype of metabolic insufficiency, characterized by mitochondrial alterations and defects in glucose uptake. Nanostring nCounter cancer metabolism assay on RNA obtained from 30 ccRCC cases revealed significant over-expression of metabolic genes even at early stage disease (pT1-2), while at pT3-4 and the locally advanced thrombi stages, there was an overall decrease in differentially expressed metabolic genes. Notably, the gene PPARGC1A was the most significantly down-regulated gene from pT1-2 to pT3-4 RCC which correlated with loss of mitochondrial function in tumour-infiltrating T-cells evident at this tumour stage. Down-regulation of PPARGC1A into stage pT3-4 may be the 'tipping-point' in RCC disease progression, modulating immune activity in ccRCC and potentially reducing the efficacy of immunotherapies in RCC and poorer patient outcomes.
    Keywords:  Renal Cell carcinoma; T-cell exhaustion metabolic
    DOI:  https://doi.org/10.1007/s00262-023-03558-5
  7. Adv Drug Deliv Rev. 2023 Nov 05. pii: S0169-409X(23)00437-4. [Epub ahead of print] 115122
    Engineering metabolism to modulate immunity.
    Senta M Kapnick, Corinne A Martin, Christopher M Jewell.
      Metabolic programming and reprogramming have emerged as pivotal mechanisms for altering immune cell function. Thus, immunometabolism has become an attractive target area for treatment of immune-mediated disorders. Nonetheless, many hurdles to delivering metabolic cues persist. In this review, we consider how biomaterials are poised to transform manipulation of immune cell metabolism through integrated control of metabolic configurations to affect outcomes in autoimmunity, regeneration, transplant, and cancer. We emphasize the features of nanoparticles and other biomaterials that permit delivery of metabolic cues to the intracellular compartment of immune cells, or strategies for altering signals in the extracellular space. We then provide perspectives on the potential for reciprocal regulation of immunometabolism by the physical properties of materials themselves. Lastly, opportunities for clinical translation are highlighted. This discussion contributes to our understanding of immunometabolism, biomaterials-based strategies for altering metabolic configurations in immune cells, and emerging concepts in this evolving field.
    Keywords:  biomaterials; immune engineering; immunometabolism
    DOI:  https://doi.org/10.1016/j.addr.2023.115122
  8. J Immunol. 2023 Nov 10. pii: ji2300248. [Epub ahead of print]
    SIKs Regulate HDAC7 Stabilization and Cytokine Recall in Late-Stage T Cell Effector Differentiation.
    Rachel S Helms, Alberto Marin-Gonzalez, Chirag H Patel, Im-Hong Sun, Jiayu Wen, Robert D Leone, Bridget Duvall, Run-Duo Gao, Taekjip Ha, Takashi Tsukamoto, Barbara S Slusher, Joel L Pomerantz, Jonathan D Powell.
      Understanding the mechanisms underlying the acquisition and maintenance of effector function during T cell differentiation is important to unraveling how these processes can be dysregulated in the context of disease and manipulated for therapeutic intervention. In this study, we report the identification of a previously unappreciated regulator of murine T cell differentiation through the evaluation of a previously unreported activity of the kinase inhibitor, BioE-1197. Specifically, we demonstrate that liver kinase B1 (LKB1)-mediated activation of salt-inducible kinases epigenetically regulates cytokine recall potential in effector CD8+ and Th1 cells. Evaluation of this phenotype revealed that salt-inducible kinase-mediated phosphorylation-dependent stabilization of histone deacetylase 7 (HDAC7) occurred during late-stage effector differentiation. HDAC7 stabilization increased nuclear HDAC7 levels, which correlated with total and cytokine loci-specific reductions in the activating transcription mark histone 3 lysine 27 acetylation (H3K27Ac). Accordingly, HDAC7 stabilization diminished transcriptional induction of cytokine genes upon restimulation. Inhibition of this pathway during differentiation produced effector T cells epigenetically poised for enhanced cytokine recall. This work identifies a previously unrecognized target for enhancing effector T cell functionality.
    DOI:  https://doi.org/10.4049/jimmunol.2300248
  9. Front Immunol. 2023 ;14 1298004
    From aging to long COVID: exploring the convergence of immunosenescence, inflammaging, and autoimmunity.
    Ludmila Müller, Svetlana Di Benedetto.
      The process of aging is accompanied by a dynamic restructuring of the immune response, a phenomenon known as immunosenescence. This mini-review navigates through the complex landscape of age-associated immune changes, chronic inflammation, age-related autoimmune tendencies, and their potential links with immunopathology of Long COVID. Immunosenescence serves as an introductory departure point, elucidating alterations in immune cell profiles and their functional dynamics, changes in T-cell receptor signaling, cytokine network dysregulation, and compromised regulatory T-cell function. Subsequent scrutiny of chronic inflammation, or "inflammaging," highlights its roles in age-related autoimmune susceptibilities and its potential as a mediator of the immune perturbations observed in Long COVID patients. The introduction of epigenetic facets further amplifies the potential interconnections. In this compact review, we consider the dynamic interactions between immunosenescence, inflammation, and autoimmunity. We aim to explore the multifaceted relationships that link these processes and shed light on the underlying mechanisms that drive their interconnectedness. With a focus on understanding the immunological changes in the context of aging, we seek to provide insights into how immunosenescence and inflammation contribute to the emergence and progression of autoimmune disorders in the elderly and may serve as potential mediator for Long COVID disturbances.
    Keywords:  SARS-CoV-2; aging; autoimmunity; epigenetics; immunosenescence; inflammaging; long COVID
    DOI:  https://doi.org/10.3389/fimmu.2023.1298004
  10. Cancer Discov. 2023 Nov 10. OF1
    Transposable Element Signatures Define Stages of T-cell Exhaustion.
      Differential expression of transposable elements occurs during T-cell exhaustion and reactivation.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-180
  11. Nat Commun. 2023 Nov 04. 14(1): 7098
    c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8+ T cell immunity.
    Asif A Dar, Dale D Kim, Scott M Gordon, Kathleen Klinzing, Siera Rosen, Ipsita Guha, Nadia Porter, Yohaniz Ortega, Katherine S Forsyth, Jennifer Roof, Hossein Fazelinia, Lynn A Spruce, Laurence C Eisenlohr, Edward M Behrens, Paula M Oliver.
      During infection, virus-specific CD8+ T cells undergo rapid bursts of proliferation and differentiate into effector cells that kill virus-infected cells and reduce viral load. This rapid clonal expansion can put T cells at significant risk for replication-induced DNA damage. Here, we find that c-Myc links CD8+ T cell expansion to DNA damage response pathways though the E3 ubiquitin ligase, Cullin 4b (Cul4b). Following activation, c-Myc increases the levels of Cul4b and other members of the Cullin RING Ligase 4 (CRL4) complex. Despite expressing c-Myc at high levels, Cul4b-deficient CD8+ T cells do not expand and clear the Armstrong strain of lymphocytic choriomeningitis virus (LCMV) in vivo. Cul4b-deficient CD8+ T cells accrue DNA damage and succumb to proliferative catastrophe early after antigen encounter. Mechanistically, Cul4b knockout induces an accumulation of p21 and Cyclin E2, resulting in replication stress. Our data show that c-Myc supports cell proliferation by maintaining genome stability via Cul4b, thereby directly coupling these two interdependent pathways. These data clarify how CD8+ T cells use c-Myc and Cul4b to sustain their potential for extraordinary population expansion, longevity and antiviral responses.
    DOI:  https://doi.org/10.1038/s41467-023-42765-7
  12. Front Immunol. 2023 ;14 1280144
    Immune cells are associated with mortality: the Health and Retirement Study.
    Gokul Seshadri, Sithara Vivek, Anna Prizment, Eileen M Crimmins, Eric T Klopack, Jessica Faul, Weihua Guan, Helen C S Meier, Bharat Thyagarajan.
      Introduction: Age-related immunosenescence is characterized by changes in immune cell subsets and is associated with mortality. However, since immunosenescence is associated with other concurrent age-related changes such as inflammation and multi-organ dysfunction, it is unclear whether the association between age-related immunosenescence and mortality is independent of other concurrent age-related changes. To address these limitations, we evaluated the independent association between immune cell subsets and mortality after adjustment for age-related inflammation and biologic age.Methods: Data for this study was obtained from the 2016 interview of the Health and Retirement Study (N=6802). Cox proportional hazards regression models were used to estimate the association between 25 immune cell subsets (11 T-cell subsets, 4 B-cell subsets, 3 monocyte subsets, 3 natural killer cell subsets, 3 dendritic cell subsets, and neutrophils) and 4-year mortality adjusting for covariates such as the Klemera-Doubal algorithm biological age, chronological age, gender, race/ethnicity, BMI, smoking status, comorbidity index, CMV seropositivity, and inflammatory latent variable comprising C-reactive protein, and 4 cytokines (interleukin-10, interleukin-1 receptor antagonist, interleukin-6, and soluble tumor necrosis factor).
    Results: Four hundred and seventy-six participants died during the study period with an overall median follow up time of 2.5 years. After controlling for covariates and adjustment for sample-weights, total T cells [HR: 0.86, p=0.004], NK CD56LO cells [HR: 0.88, p=0.005], and neutrophils [HR: 1.22, p=0.004] were significantly associated with mortality.
    Conclusions: These findings support the idea that an aging immune system is associated with short-term mortality independent of age-related inflammation or other age-related measures of physiological dysfunction. If replicated in other external cohorts, these findings could identify novel targets for both monitoring and intervention to reduce the age-related mortality.
    Keywords:  B-cells; Health and Retirement Study; NK cells; T-cells; dendritic cells; inflammation; mortality; neutrophils
    DOI:  https://doi.org/10.3389/fimmu.2023.1280144
  13. Cancer Discov. 2023 Nov 07.
    SUV39H1 Ablation Enhances Long-Term CAR-T Function in Solid Tumors.
    Sheila Lopez-Cobo, Jaime R Fuentealba, Paul Gueguen, Pierre-Emmanuel Bonte, Kyriaki Tsalkitzi, Irena Chacon, Salome Glauzy, Armelle Bohineust, Ariane Biquand, Lisseth Silva, Zelia Gouveia, Christel Goudot, Franck Perez, Michael Saitakis, Sebastian Amigorena.
      Failure of adoptive T cell therapies in cancer patients is linked to limited T cell expansion and persistence, even in memory-prone 41BB-(BBz)-based chimeric antigen receptor (CAR) T cells. We show here that BBz-CAR T cell stem/memory differentiation and persistence can be enhanced through epigenetic manipulation of the histone 3 lysine 9 tri-methylation (H3K9me3) pathway. Inactivation of the H3K9 tri-methyltransferase SUV39H1 enhances BBz-CAR T cell long-term persistence, protecting mice against tumor relapses and rechallenges in lung and disseminated solid tumor models up to several months after CAR T cell infusion. Single-cell transcriptomic (scRNAseq) and chromatin opening (scATACseq) analyses of tumor infiltrating CAR T cells show early reprogramming into self-renewing, stem-like populations with decreased expression of dysfunction genes in all T cell subpopulations. Therefore, epigenetic manipulation of H3K9 methylation by SUV39H1 optimizes long-term functional persistence of BBz-CAR T cells, limiting relapses and providing protection against tumor rechallenges.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-1350
  14. Life Sci. 2023 Nov 01. pii: S0024-3205(23)00864-0. [Epub ahead of print]334 122229
    Gut microbiota-mediated IL-22 alleviates metabolic inflammation.
    Kaijun Wang, Miao Zhou, Hongbin Si, Jie Ma.
      Low-grade chronic inflammation, also known as metabolic inflammation, promotes the development of metabolic diseases. Increasing evidence suggests that changes in gut microbes and metabolites disrupt the integrity of the gut barrier and exert significant effects on the metabolism of various tissues, including the liver and adipose tissue, thereby contributing to metabolic inflammation. We observed that IL-22 is a key signaling molecule that serves as a bridge between intestinal microbes and the host, effectively alleviating metabolic inflammation by modulating the host immunomodulatory network. Here, we focused on elucidating the underlying mechanisms by which the gut microbiota and their metabolites reduce inflammation via IL-22, highlighting the favorable impact of IL-22 on metabolic inflammation. Furthermore, we discuss the potential of IL-22 as a therapeutic target for the management of metabolic inflammation and related diseases.
    Keywords:  Disease; Gut microbiota; IL-22; Inflammation; Metabolism
    DOI:  https://doi.org/10.1016/j.lfs.2023.122229
  15. Sci Immunol. 2023 Nov 10. 8(89): eadi9066
    Zfp281 and Zfp148 control CD4+ T cell thymic development and TH2 functions.
    Laura B Chopp, Xiaoliang Zhu, Yayi Gao, Jia Nie, Jatinder Singh, Parimal Kumar, Kelly Z Young, Shil Patel, Caiyi Li, Mariah Balmaceno-Criss, Melanie S Vacchio, Michael M Wang, Ferenc Livak, Juanita L Merchant, Lie Wang, Michael C Kelly, Jinfang Zhu, Rémy Bosselut.
      How CD4+ lineage gene expression is initiated in differentiating thymocytes remains poorly understood. Here, we show that the paralog transcription factors Zfp281 and Zfp148 control both this process and cytokine expression by T helper cell type 2 (TH2) effector cells. Genetic, single-cell, and spatial transcriptomic analyses showed that these factors promote the intrathymic CD4+ T cell differentiation of class II major histocompatibility complex (MHC II)-restricted thymocytes, including expression of the CD4+ lineage-committing factor Thpok. In peripheral T cells, Zfp281 and Zfp148 promoted chromatin opening at and expression of TH2 cytokine genes but not of the TH2 lineage-determining transcription factor Gata3. We found that Zfp281 interacts with Gata3 and is recruited to Gata3 genomic binding sites at loci encoding Thpok and TH2 cytokines. Thus, Zfp148 and Zfp281 collaborate with Gata3 to promote CD4+ T cell development and TH2 cell responses.
    DOI:  https://doi.org/10.1126/sciimmunol.adi9066
This page is being maintained by Thomas Krichel. It was last updated on 2023‒11‒12 at 8:51.