bims-imseme 2022-01-02 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2022–01–02
eight papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Sirtuin 5 is Dispensable for CD8+ T Cell Effector and Memory Differentiation.
Macrophages are metabolically heterogeneous within the tumor microenvironment.
Targeting the Molecular & Cellular Pillars of Human Aging with Exercise.
Epigenetic regulation of T cell development.
The mitochondrial DNA constitution shaping T-cell immunity in patients with rectal cancer at high risk of metastatic progression.
Senescence-induced changes in CD4 T cell differentiation can be alleviated by treatment with senolytics.
T cell fat catabolism: A novel target for kynurenine?
Microbiome and Human Aging: Probiotic and Prebiotic Potentials in Longevity, Skin Health and Cellular Senescence.

Front Cell Dev Biol. 2021 ;9 761193

Sirtuin 5 is Dispensable for CD8+ T Cell Effector and Memory Differentiation.

Qianqian Duan, Jiying Ding, Fangfang Li, Xiaowei Liu, Yunan Zhao, Hongxiu Yu, Yong Liu, Lianjun Zhang.

  CD8+ T cell effector and memory differentiation is tightly controlled at multiple levels including transcriptional, metabolic, and epigenetic regulation. Sirtuin 5 (SIRT5) is a protein deacetylase mainly located at mitochondria, but it remains unclear whether SIRT5 plays key roles in regulating CD8+ T cell effector or memory formation. Herein, with adoptive transfer of Sirt5+/+ or Sirt5-/- OT-1 cells and acute Listeria monocytogenes infection model, we demonstrate that SIRT5 deficiency does not affect CD8+ T cell effector function and that SIRT5 is not required for CD8+ T cell memory formation. Moreover, the recall response of SIRT5 deficient memory CD8+ T cells is comparable with Sirt5+/+ memory CD8+ T cells. Together, these observations suggest that SIRT5 is dispensable for the effector function and memory differentiation of CD8+ T cells.

Keywords:  CD8 T cell; effector T cell; infecion; memory T cell; sirtuin 5 (SIRT5)

DOI:  https://doi.org/10.3389/fcell.2021.761193
Cell Rep. 2021 Dec 28. pii: S2211-1247(21)01671-5. [Epub ahead of print]37(13): 110171

Macrophages are metabolically heterogeneous within the tumor microenvironment.

Xenia Geeraerts, Juan Fernández-Garcia, Felix J Hartmann, Kyra E de Goede, Liesbet Martens, Yvon Elkrim, Ayla Debraekeleer, Benoit Stijlemans, Anke Vandekeere, Gianmarco Rinaldi, Riet De Rycke, Mélanie Planque, Dorien Broekaert, Elisa Meinster, Emile Clappaert, Pauline Bardet, Aleksandar Murgaski, Conny Gysemans, Frank Aboubakar Nana, Yvan Saeys, Sean C Bendall, Damya Laoui, Jan Van den Bossche, Sarah-Maria Fendt, Jo A Van Ginderachter.

  Macrophages are often prominently present in the tumor microenvironment, where distinct macrophage populations can differentially affect tumor progression. Although metabolism influences macrophage function, studies on the metabolic characteristics of ex vivo tumor-associated macrophage (TAM) subsets are rather limited. Using transcriptomic and metabolic analyses, we now reveal that pro-inflammatory major histocompatibility complex (MHC)-IIhi TAMs display a hampered tricarboxylic acid (TCA) cycle, while reparative MHC-IIlo TAMs show higher oxidative and glycolytic metabolism. Although both TAM subsets rapidly exchange lactate in high-lactate conditions, only MHC-IIlo TAMs use lactate as an additional carbon source. Accordingly, lactate supports the oxidative metabolism in MHC-IIlo TAMs, while it decreases the metabolic activity of MHC-IIhi TAMs. Lactate subtly affects the transcriptome of MHC-IIlo TAMs, increases L-arginine metabolism, and enhances the T cell suppressive capacity of these TAMs. Overall, our data uncover the metabolic intricacies of distinct TAM subsets and identify lactate as a carbon source and metabolic and functional regulator of TAMs.

Keywords:  TCA cycle break; immunometabolism; immunosuppression; lactate; macrophage metabolism; metabolomics; non-small-cell lung carcinoma; single-cell metabolic profiling; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.celrep.2021.110171
FEBS J. 2021 Dec 30.

Targeting the Molecular & Cellular Pillars of Human Aging with Exercise.

Jorming Goh, Esther Wong, Janjira Soh, Andrea Maier, Brian Kennedy.

  Biological aging is the main driver of age-associated chronic diseases. In 2014, the United States National Institute of Aging (NIA) sponsored a meeting between several investigators in the field of aging biology, who identified 7 biological pillars of aging and a consensus review, "Geroscience: Linking Aging to Chronic Disease," was published. The pillars of aging demonstrated the conservation of aging pathways in diverse model organisms and thus, represent a useful framework with which to study human aging. In this present review, we revisit the 7 pillars of aging from the perspective of exercise and discuss how regular physical exercise can modulate these pillars to stave off age-related chronic diseases and maintain functional capacity.

Keywords:  aging; disruption in proteostasis; dysregulated stress response; epigenetic drift; inflammaging; macromolecular damage; metabolic dysregulation; stem cell exhaustion

DOI:  https://doi.org/10.1111/febs.16337
Int Rev Immunol. 2021 Dec 30. 1-9

Epigenetic regulation of T cell development.

Avik Dutta, Harini Venkataganesh, Paul E Love.

  Epigenetic regulators are pivotal factors that influence and control T cell development. Recent findings continue to reveal additional elements of epigenetic modifications that play significant and crucial roles at different stages of T cell development. Through gaining a better understanding of the various epigenetic factors that influence the formation and survival of maturing T cells, new therapies can potentially be developed to combat diseases caused by dysregulated epigenetic chromatin modifications. In this review, we summarize the recent studies which shed light on the epigenetic regulation of T cell development especially at the critical stage of β-selection.

Keywords:  Epigenetics; T cell development; thymocytes; β-selection

DOI:  https://doi.org/10.1080/08830185.2021.2022661
Clin Transl Oncol. 2021 Dec 27.

The mitochondrial DNA constitution shaping T-cell immunity in patients with rectal cancer at high risk of metastatic progression.

P A Bousquet, S Meltzer, A J Fuglestad, T Lüders, Y Esbensen, H V Juul, C Johansen, L G Lyckander, T Bjørnetrø, E M Inderberg, C Kersten, K R Redalen, A H Ree.

   PURPOSE: A significant percentage of colorectal cancer patients proceeds to metastatic disease. We hypothesised that mitochondrial DNA (mtDNA) polymorphisms, generated by the high mtDNA mutation rate of energy-demanding clonal immune cell expansions and assessable in peripheral blood, reflect how efficiently systemic immunity impedes metastasis.
PATIENTS AND METHODS: We studied 44 rectal cancer patients from a population-based prospective biomarker study, given curative-intent neoadjuvant radiation and radical surgery for high-risk tumour stage and followed for metastatic failure. Blood specimens were sampled at the time of diagnosis and analysed for the full-length mtDNA sequence, composition of immune cell subpopulations and damaged serum mtDNA.
RESULTS: Whole blood total mtDNA variant number above the median value for the study cohort, coexisting with an mtDNA non-H haplogroup, was representative for the mtDNA of circulating immune cells and associated with low risk of a metastatic event. Abundant mtDNA variants correlated with proliferating helper T cells and cytotoxic effector T cells in the circulation. Patients without metastatic progression had high relative levels of circulating tumour-targeting effector T cells and, of note, the naïve (LAG-3+) helper T-cell population, with the proportion of LAG-3+ cells inversely correlating with cell-free damaged mtDNA in serum known to cause antagonising inflammation.
CONCLUSION: Numerous mtDNA polymorphisms in peripheral blood reflected clonal expansion of circulating helper and cytotoxic T-cell populations in patients without metastatic failure. The statistical associations suggested that patient's constitutional mtDNA manifests the helper T-cell capacity to mount immunity that controls metastatic susceptibility.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01816607; registration date: 22 March 2013.

Keywords:  CD4; Colorectal cancer; Immune cells; Metastasis; Mitochondrial DNA

DOI:  https://doi.org/10.1007/s12094-021-02756-w
Aging Cell. 2021 Dec 27. e13525

Senescence-induced changes in CD4 T cell differentiation can be alleviated by treatment with senolytics.

Erica C Lorenzo, Blake L Torrance, Spencer R Keilich, Iman Al-Naggar, Andrew Harrison, Ming Xu, Jenna M Bartley, Laura Haynes.

  Aging and senescence impact CD4 T helper cell (Th) subset differentiation during influenza infection. In the lungs of infected aged mice, there were significantly greater percentages of Th cells expressing the transcription factor FoxP3, indicative of regulatory CD4 T cells (Treg), when compared to young. TGF-beta levels, which drive FoxP3 expression, were also higher in the bronchoalveolar lavage of aged mice and blocking TGF-beta reduced the percentage of FoxP3+ Th in aged lungs during influenza infection. Since TGF-beta can be the product of senescent cells, these were targeted by treatment with senolytic drugs. Treatment of aged mice with senolytics prior to influenza infection restored the differentiation of Th cells in those aged mice to a more youthful phenotype with fewer Th cells expressing FoxP3. In addition, treatment with senolytic drugs induced differentiation of aged Th toward a healing Type 2 phenotype, which promotes a return to homeostasis. These results suggest that senescent cells, via production of cytokines such as TGF-beta, have a significant impact on Th differentiation.

Keywords:  T cells; aging; influenza; senescence; senolytics

DOI:  https://doi.org/10.1111/acel.13525
EBioMedicine. 2021 Dec 23. pii: S2352-3964(21)00573-9. [Epub ahead of print]75 103779

T cell fat catabolism: A novel target for kynurenine?

Paolo Puccetti, Francesca Fallarino.

DOI: https://doi.org/10.1016/j.ebiom.2021.103779
Nutrients. 2021 Dec 18. pii: 4550. [Epub ahead of print]13(12):

Microbiome and Human Aging: Probiotic and Prebiotic Potentials in Longevity, Skin Health and Cellular Senescence.

Jacqueline Lena Boyajian, Merry Ghebretatios, Sabrina Schaly, Paromita Islam, Satya Prakash.

  The role of the microbiome in human aging is important: the microbiome directly impacts aging through the gastrointestinal system. However, the microbial impact on skin has yet to be fully understood. For example, cellular senescence is an intrinsic aging process that has been recently associated with microbial imbalance. With age, cells become senescent in response to stress wherein they undergo irreversible growth arrest while maintaining high metabolic activity. An accumulation of senescent cells has been linked to various aging and chronic pathologies due to an overexpression of the senescence-associated secretory phenotype (SASP) comprised of proinflammatory cytokines, chemokines, growth factors, proteases, lipids and extracellular matrix components. In particular, dermatological disorders may be promoted by senescence as the skin is a common site of accumulation. The gut microbiota influences cellular senescence and skin disruption through the gut-skin axis and secretion of microbial metabolites. Metabolomics can be used to identify and quantify metabolites involved in senescence. Moreover, novel anti-senescent therapeutics are warranted given the poor safety profiles of current pharmaceutical drugs. Probiotics and prebiotics may be effective alternatives, considering the relationship between the microbiome and healthy aging. However, further research on gut composition under a senescent status is needed to develop immunomodulatory therapies.

Keywords:  cellular senescence; disease; dysbiosis; gut microbiome; microbial metabolites; nutrition; prebiotics; probiotics; skin

DOI:  https://doi.org/10.3390/nu13124550