bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023‒09‒17
twelve papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Proteostasis in T cell aging.
  2. HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer.
  3. Activation of the transcription factor NFAT5 in the tumor microenvironment enforces CD8+ T cell exhaustion.
  4. Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation.
  5. N6-methyladenosine regulator YTHDF1 represses the CD8 + T cell-mediated antitumor immunity and ferroptosis in prostate cancer via m6A/PD-L1 manner.
  6. Disorder-based T cell developmental order.
  7. Geroprotective interventions converge on gene expression programs of reduced inflammation and restored fatty acid metabolism.
  8. CD160 Signaling Is Essential for CD8+ T Cell Memory Formation via Upregulation of 4-1BB.
  9. Editorial: Modulation of T-cell function and survival by the tumor microenvironment.
  10. Ascorbic acid modulates immune responses through Jumonji-C domain containing histone demethylases and Ten eleven translocation (TET) methylcytosine dioxygenase.
  11. Cold-stimulated brown adipose tissue activation is related to changes in serum metabolites relevant to NAD+ metabolism in humans.
  12. Treg-targeted IL-2/anti-IL-2 complex controls graft-versus-host disease and supports anti-tumor effect in allogeneic hematopoietic stem cell transplantation.
  1. Semin Immunol. 2023 Sep 12. pii: S1044-5323(23)00129-X. [Epub ahead of print]70 101838
    Proteostasis in T cell aging.
    A Elisabeth Gressler, Houfu Leng, Heidi Zinecker, Anna Katharina Simon.
      Aging leads to a decline in immune cell function, which leaves the organism vulnerable to infections and age-related multimorbidities. One major player of the adaptive immune response are T cells, and recent studies argue for a major role of disturbed proteostasis contributing to reduced function of these cells upon aging. Proteostasis refers to the state of a healthy, balanced proteome in the cell and is influenced by synthesis (translation), maintenance and quality control of proteins, as well as degradation of damaged or unwanted proteins by the proteasome, autophagy, lysosome and cytoplasmic enzymes. This review focuses on molecular processes impacting on proteostasis in T cells, and specifically functional or quantitative changes of each of these upon aging. Importantly, we describe the biological consequences of compromised proteostasis in T cells, which range from impaired T cell activation and function to enhancement of inflamm-aging by aged T cells. Finally, approaches to improve proteostasis and thus rejuvenate aged T cells through pharmacological or physical interventions are discussed.
    Keywords:  Aging; Degradation; Inflamm-aging; Proteostasis; T cell; Translation
    DOI:  https://doi.org/10.1016/j.smim.2023.101838
  2. Nat Commun. 2023 Sep 13. 14(1): 5631
    HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer.
    Emily N Neubert, Julia M DeRogatis, Sloan A Lewis, Karla M Viramontes, Pedro Ortega, Monique L Henriquez, Rémi Buisson, Ilhem Messaoudi, Roberto Tinoco.
      Chronic infections and cancers evade the host immune system through mechanisms that induce T cell exhaustion. The heterogeneity within the exhausted CD8+ T cell pool has revealed the importance of stem-like progenitor (Tpex) and terminal (Tex) exhausted T cells, although the mechanisms underlying their development are not fully known. Here we report High Mobility Group Box 2 (HMGB2) protein expression is upregulated and sustained in exhausted CD8+ T cells, and HMGB2 expression is critical for their differentiation. Through epigenetic and transcriptional programming, we identify HMGB2 as a cell-intrinsic regulator of the differentiation and maintenance of Tpex cells during chronic viral infection and in tumors. Despite Hmgb2-/- CD8+ T cells expressing TCF-1 and TOX, these master regulators were unable to sustain Tpex differentiation and long-term survival during persistent antigen. Furthermore, HMGB2 also had a cell-intrinsic function in the differentiation and function of memory CD8+ T cells after acute viral infection. Our findings show that HMGB2 is a key regulator of CD8+ T cells and may be an important molecular target for future T cell-based immunotherapies.
    DOI:  https://doi.org/10.1038/s41467-023-41352-0
  3. Nat Immunol. 2023 Sep 14.
    Activation of the transcription factor NFAT5 in the tumor microenvironment enforces CD8+ T cell exhaustion.
    Laure Tillé, Daniela Cropp, Mélanie Charmoy, Patrick Reichenbach, Massimo Andreatta, Tania Wyss, Gabrielle Bodley, Isaac Crespo, Sina Nassiri, Joao Lourenco, Marine M Leblond, Cristina Lopez-Rodriguez, Daniel E Speiser, George Coukos, Melita Irving, Santiago J Carmona, Werner Held, Grégory Verdeil.
      Persistent exposure to antigen during chronic infection or cancer renders T cells dysfunctional. The molecular mechanisms regulating this state of exhaustion are thought to be common in infection and cancer, despite obvious differences in their microenvironments. Here we found that NFAT5, an NFAT family transcription factor that lacks an AP-1 docking site, was highly expressed in exhausted CD8+ T cells in the context of chronic infections and tumors but was selectively required in tumor-induced CD8+ T cell exhaustion. Overexpression of NFAT5 in CD8+ T cells reduced tumor control, while deletion of NFAT5 improved tumor control by promoting the accumulation of tumor-specific CD8+ T cells that had reduced expression of the exhaustion-associated proteins TOX and PD-1 and produced more cytokines, such as IFNɣ and TNF, than cells with wild-type levels of NFAT5, specifically in the precursor exhausted PD-1+TCF1+TIM-3-CD8+ T cell population. NFAT5 did not promote T cell exhaustion during chronic infection with clone 13 of lymphocytic choriomeningitis virus. Expression of NFAT5 was induced by TCR triggering, but its transcriptional activity was specific to the tumor microenvironment and required hyperosmolarity. Thus, NFAT5 promoted the exhaustion of CD8+ T cells in a tumor-selective fashion.
    DOI:  https://doi.org/10.1038/s41590-023-01614-x
  4. Nat Commun. 2023 Sep 11. 14(1): 5585
    Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation.
    Alexandria C Wells, Kaito A Hioki, Constance C Angelou, Adam C Lynch, Xueting Liang, Daniel J Ryan, Iris Thesmar, Saule Zhanybekova, Saulius Zuklys, Jacob Ullom, Agnes Cheong, Jesse Mager, Georg A Hollander, Elena L Pobezinskaya, Leonid A Pobezinsky.
      The success of the CD8 T cell-mediated immune response against infections and tumors depends on the formation of a long-lived memory pool, and the protection of effector cells from exhaustion. The advent of checkpoint blockade therapy has significantly improved anti-tumor therapeutic outcomes by reversing CD8 T cell exhaustion, but fails to generate effector cells with memory potential. Here, using in vivo mouse models, we show that let-7 miRNAs determine CD8 T cell fate, where maintenance of let-7 expression during early cell activation results in memory CD8 T cell formation and tumor clearance. Conversely, let-7-deficiency promotes the generation of a terminal effector population that becomes vulnerable to exhaustion and cell death in immunosuppressive environments and fails to reject tumors. Mechanistically, let-7 restrains metabolic changes that occur during T cell activation through the inhibition of the PI3K/AKT/mTOR signaling pathway and production of reactive oxygen species, potent drivers of terminal differentiation and exhaustion. Thus, our results reveal a role for let-7 in the time-sensitive support of memory formation and the protection of effector cells from exhaustion. Overall, our data suggest a strategy in developing next-generation immunotherapies by preserving the multipotency of effector cells rather than enhancing the efficacy of differentiation.
    DOI:  https://doi.org/10.1038/s41467-023-40959-7
  5. Apoptosis. 2023 Sep 12.
    N6-methyladenosine regulator YTHDF1 represses the CD8 + T cell-mediated antitumor immunity and ferroptosis in prostate cancer via m6A/PD-L1 manner.
    Yibing Wang, Peng Jin, Xia Wang.
      Increasing data and literature have illustrated that tumor immune escape represents a major source of tumor formation and recrudesce. Besides, novel findings also indicate that RNA N6-methyladenosine (m6A) participates in the human cancer immune escape. Here, our study investigated the functions of m6A reader YTHDF1 in prostate cancer (PCa) immune response and explored the functional mechanism. Results reported that YTHDF1 up-regulated in PCa samples and was closely correlated to poor clinical prognosis. Functionally, YTHDF1 inhibited the killing activity of CD8 + T cells to PCa cells, and moreover mitigated the ferroptosis. Mechanistically, PD-L1 acted as the target of YTHDF1, and YTHDF1 upregulated the transcriptional activity of PD-L1 mRNA. Collectively, YTHDF1 promoted functional PD-L1 partially through enhancing its transcriptional stability, which was necessary for PCa cells to evade effector T cell cytotoxicity and CD8 + T cells mediated ferroptosis. In conclusion, these findings indicate that YTHDF1 represses the CD8 + T cell-mediated antitumor immunity and ferroptosis in PCa via m6A-PD-L1 manner, which may provide novel insight for PCa immunotherapy.
    Keywords:  Immune escape; N6-methyladenosine; PD-L1; Prostate cancer; YTHDF1
    DOI:  https://doi.org/10.1007/s10495-023-01885-7
  6. Nat Immunol. 2023 Sep 14.
    Disorder-based T cell developmental order.
    Shuai Liu, Keji Zhao.
      
    DOI:  https://doi.org/10.1038/s41590-023-01623-w
  7. Geroscience. 2023 Sep 12.
    Geroprotective interventions converge on gene expression programs of reduced inflammation and restored fatty acid metabolism.
    Tomer Landsberger, Ido Amit, Uri Alon.
      Understanding the mechanisms of geroprotective interventions is central to aging research. We compare four prominent interventions: senolysis, caloric restriction, in vivo partial reprogramming, and heterochronic parabiosis. Using published mice transcriptomic data, we juxtapose these interventions against normal aging. We find a gene expression program common to all four interventions, in which inflammation is reduced and several metabolic processes, especially fatty acid metabolism, are increased. Normal aging exhibits the inverse of this signature across multiple organs and tissues. A similar inverse signature arises in three chronic inflammation disease models in a non-aging context, suggesting that the shift in metabolism occurs downstream of inflammation. Chronic inflammation is also shown to accelerate transcriptomic age. We conclude that a core mechanism of geroprotective interventions acts through the reduction of inflammation with downstream effects that restore fatty acid metabolism. This supports the notion of directly targeting genes associated with these pathways to mitigate age-related deterioration.
    Keywords:  Aging; Geroprotective interventions; Inflammation; Longevity; Rejuvenation; Transcriptomics
    DOI:  https://doi.org/10.1007/s11357-023-00915-1
  8. J Immunol. 2023 Sep 11. pii: ji2200792. [Epub ahead of print]
    CD160 Signaling Is Essential for CD8+ T Cell Memory Formation via Upregulation of 4-1BB.
    Linxia Zhang, Anli Zhang, Xinyu Zhu, Xinmei Tian, Jiaohan Guo, Qian He, Lingyan Zhu, Songhua Yuan, Chen Zhao, Xiaoyan Zhang, Jianqing Xu.
      A better understanding of the regulatory mechanisms governing the development of memory CD8+ T cells could provide instructive insights into vaccination strategies and T cell-based immunotherapies. In this article, we showed that CD160 surface protein is required for CD8+ T cell memory formation. In the response to acute lymphocytic choriomeningitis virus infection in a mouse model, CD160 ablation resulted in the failure of the development of all three memory CD8+ T cell subsets (central, effective, and tissue-resident memory), concomitant with a skewed differentiation into short-lived effector T cells. Such memory-related defect was manifested by a diminished protection from viral rechallenge. Mechanistically, CD160 deficiency led to downregulation of 4-1BB in activated CD8+ T cells, which contributes to the impaired cell survival and decreased respiratory capacity. The nexus between CD160 and 4-1BB was substantiated by the observation that ectopic introduction of 4-1BB was able to largely complement the loss of CD160 in memory CD8+ T cell development. Collectively, our studies discovered that CD160, once thought to be a coinhibitor of T cell signaling, is an essential promoter of memory CD8+ T cell development via activation of the costimulatory molecule 4-1BB.
    DOI:  https://doi.org/10.4049/jimmunol.2200792
  9. Front Cell Dev Biol. 2023 ;11 1271772
    Editorial: Modulation of T-cell function and survival by the tumor microenvironment.
    Kristian M Hargadon, Courtney M Lappas, Shahrzad Jalali.
      
    Keywords:  T cell; cancer; immune regulation; tumor immunity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2023.1271772
  10. Bioessays. 2023 Sep 11. e2300035
    Ascorbic acid modulates immune responses through Jumonji-C domain containing histone demethylases and Ten eleven translocation (TET) methylcytosine dioxygenase.
    Jeet Maity, Satyabrata Majumder, Ranjana Pal, Bhaskar Saha, Prabir Kumar Mukhopadhyay.
      Ascorbic acid is a redox regulator in many physiological processes. Besides its antioxidant activity, many intriguing functions of ascorbic acid in the expression of immunoregulatory genes have been suggested. Ascorbic acid acts as a co-factor for the Fe+2 -containing α-ketoglutarate-dependent Jumonji-C domain-containing histone demethylases (JHDM) and Ten eleven translocation (TET) methylcytosine dioxygenasemediated epigenetic modulation. By influencing JHDM and TET, ascorbic acid facilitates the differentiation of double negative (CD4- CD8- ) T cells to double positive (CD4+ CD8+ ) T cells and of T-helper cells to different effector subsets. Ascorbic acid modulates plasma cell differentiation and promotes early differentiation of hematopoietic stem cells (HSCs) to NK cells. These findings indicate that ascorbic acid plays a significant role in regulating both innate and adaptive immune cells, opening up new research areas in Immunonutrition. Being a water-soluble vitamin and a safe micro-nutrient, ascorbic acid can be used as an adjunct therapy for many disorders of the immune system.
    Keywords:  Ascorbic acid; Epigenetic modifications; Immunomodulation; Jumonji-C domain-containing histone demethylase (JHDM); Ten eleven translocation (TET) methylcytosine dioxygenase
    DOI:  https://doi.org/10.1002/bies.202300035
  11. Cell Rep. 2023 Sep 13. pii: S2211-1247(23)01143-9. [Epub ahead of print]42(9): 113131
    Cold-stimulated brown adipose tissue activation is related to changes in serum metabolites relevant to NAD+ metabolism in humans.
    Mueez U-Din, Vanessa D de Mello, Marjo Tuomainen, Juho Raiko, Tarja Niemi, Tobias Fromme, Anton Klåvus, Nadine Gautier, Kimmo Haimilahti, Marko Lehtonen, Karsten Kristiansen, John W Newman, Kirsi H Pietiläinen, Jussi Pihlajamäki, Ez-Zoubir Amri, Martin Klingenspor, Pirjo Nuutila, Eija Pirinen, Kati Hanhineva, Kirsi A Virtanen.
      Cold-induced brown adipose tissue (BAT) activation is considered to improve metabolic health. In murine BAT, cold increases the fundamental molecule for mitochondrial function, nicotinamide adenine dinucleotide (NAD+), but limited knowledge of NAD+ metabolism during cold in human BAT metabolism exists. We show that cold increases the serum metabolites of the NAD+ salvage pathway (nicotinamide and 1-methylnicotinamide) in humans. Additionally, individuals with cold-stimulated BAT activation have decreased levels of metabolites from the de novo NAD+ biosynthesis pathway (tryptophan, kynurenine). Serum nicotinamide correlates positively with cold-stimulated BAT activation, whereas tryptophan and kynurenine correlate negatively. Furthermore, the expression of genes involved in NAD+ biosynthesis in BAT is related to markers of metabolic health. Our data indicate that cold increases serum tryptophan conversion to nicotinamide to be further utilized by BAT. We conclude that NAD+ metabolism is activated upon cold in humans and is probably regulated in a coordinated fashion by several tissues.
    Keywords:  BAT; CP: Metabolism; NAD(+); cold exposure; human brown adipose tissue; nicotinamide; tryptophan
    DOI:  https://doi.org/10.1016/j.celrep.2023.113131
  12. Haematologica. 2023 Sep 14.
    Treg-targeted IL-2/anti-IL-2 complex controls graft-versus-host disease and supports anti-tumor effect in allogeneic hematopoietic stem cell transplantation.
    Allan Thiolat, Caroline Pilon, Pamela Caudana, Audrey Moatti, Nhu Hanh To, Christine Sedlik, Mathieu Leclerc, Sébastien Maury, Eliane Piaggio, José L Cohen.
      Modulating an immune response in opposite directions represents the holy grail in allogeneic hematopoietic stem cell transplantation (allo-HSCT) to avoid insufficient reactivity of donor T cells and hematologic malignancy relapse while controlling the potential development of graft-versus-host disease (GVHD), in which donor T cells attack the recipient's tissues. IL-2/anti-IL-2 complexes (IL2-Cxs) represents a therapeutic option to selectively accentuate or dampen the immune response. In dedicated experimental models of allo-HSCT, including also human cells injected in immunodeficient NSG mice, we evaluated side-by-side the therapeutic effect of two IL-2Cxs designed either to boost regulatory T cells (Tregs) or alternatively to activate effector T cells (Teffs), on GVHD occurrence and tumor relapse. We also evaluated the effect of the complexes on the phenotype and function of immune cells in vivo. Unexpectedly, both pro-Treg and pro-Teff IL-2Cxs prevented GVHD development. They both induced Treg expansion and reduced CD8+ T cells numbers, compared to untreated mice. However, only mice treated with the pro-Treg IL-2Cx, showed a dramatic reduction of exhausted CD8+ T cells, consistent with a potent anti-tumor effect. When evaluated on human cells, pro-Treg IL-2Cx also preferentially induced Treg expansion in vitro and in vivo, while allowing the development of a potent antitumor effect in NSG mice. Our results demonstrated the clinical relevance of using a pro-Treg, but not a pro-Teff IL2/anti-IL-2 complex to modulate alloreactivity after HSCT, while promoting a GVL effect.
    DOI:  https://doi.org/10.3324/haematol.2022.282653
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