bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022–12–04
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. [Competition between T Cells for a Finite Epidermal Niche Promotes Selective Retention of Antigen-specific Memory T Cells in the Epidermis].
  2. Metabolic determinants of tumour initiation.
  3. Phosphofructokinase P fine-tunes T regulatory cell metabolism, function, and stability in systemic autoimmunity.
  4. Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism.
  5. D-2HG comes out of its shell: Metabolic effects on the immune environment.
  6. Inhibition of glutaminolysis restores mitochondrial function in senescent stem cells.
  7. Early microbial exposure shapes adult immunity by altering CD8+ T cell development.
  8. Dietary methionine restriction improves gut microbiota composition and prevents cognitive impairment in D-galactose-induced aging mice.
  9. IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein.
  10. Nutrient deprivation and hypoxia alter T cell immune checkpoint expression: potential impact for immunotherapy.
  1. Yakugaku Zasshi. 2022 ;142(12): 1327-1332
    [Competition between T Cells for a Finite Epidermal Niche Promotes Selective Retention of Antigen-specific Memory T Cells in the Epidermis].
    Toshiro Hirai.
      Tissue-resident memory T cells are a highly abundant, non-blood circulating subset of memory T cells. These appear to be the most protective population of memory T cells at barrier surfaces. Long-term retention and survival of tissue-resident memory CD8+ T cells (Trm) is determined by tissue-derived signals, such as keratinocyte-mediated activation of transforming growth factor β (TGFβ) in the epidermis. We found that T cell clones compete for limited amounts of active TGFβ and pre-existing Trm could be replaced with newly recruited effector T cells in the epidermis. On the other hand, when effector T cells transition into Trm, the presence of cutaneous cognate antigen increases the fitness of individual Trm clones in the epidermal niche. Thus, antigen-specific Trm are more efficiently retained than bystander Trm that have not encountered cognate antigens when they compete with newly recruited effector T cells for limited active TGFβ. Therefore, competition between T cells for active TGFβ represents a selective pressure that promotes the accumulation of antigen-specific Trm cells in the epidermal niche. Furthermore, our model implies that the epidermis offers a finite niche for maintaining Trm. Although the epidermal niche of Trm cannot represent the capacity of T cell-mediated immune memory in our body, these findings might suggest a challenge for the accommodation of memory T cells specific to multiple pathogens throughout a lifetime.
    Keywords:  resident memory CD8+ T cell; skin; transforming growth factor β (TGFβ)
    DOI:  https://doi.org/10.1248/yakushi.22-00155
  2. Nat Rev Endocrinol. 2022 Nov 29.
    Metabolic determinants of tumour initiation.
    Julia S Brunner, Lydia W S Finley.
      Tumours exhibit notable metabolic alterations compared with their corresponding normal tissue counterparts. These metabolic alterations can support anabolic growth, enable survival in hostile environments and regulate gene expression programmes that promote malignant progression. Whether these metabolic changes are selected for during malignant transformation or can themselves be drivers of tumour initiation is unclear. However, intriguingly, many of the major bottlenecks for tumour initiation - control of cell fate, survival and proliferation - are all amenable to metabolic regulation. In this article, we review evidence demonstrating a critical role for metabolic pathways in processes that support the earliest stages of tumour development. We discuss how cell-intrinsic factors, such as the cell of origin or transforming oncogene, and cell-extrinsic factors, such as local nutrient availability, promote or restrain tumour initiation. Deeper insight into how metabolic pathways control tumour initiation will improve our ability to design metabolic interventions to limit tumour incidence.
    DOI:  https://doi.org/10.1038/s41574-022-00773-5
  3. Sci Adv. 2022 Dec 02. 8(48): eadc9657
    Phosphofructokinase P fine-tunes T regulatory cell metabolism, function, and stability in systemic autoimmunity.
    Marc Scherlinger, Wenliang Pan, Ryo Hisada, Afroditi Boulougoura, Nobuya Yoshida, Milena Vukelic, Masataka Umeda, Suzanne Krishfield, Maria G Tsokos, George C Tsokos.
      Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by defective regulatory T (Treg) cells. Here, we demonstrate that a T cell-specific deletion of calcium/calmodulin-dependent protein kinase 4 (CaMK4) improves disease in B6.lpr lupus-prone mice and expands Treg cells. Mechanistically, CaMK4 phosphorylates the glycolysis rate-limiting enzyme 6-phosphofructokinase, platelet type (PFKP) and promotes aerobic glycolysis, while its end product fructose-1,6-biphosphate suppresses oxidative metabolism. In Treg cells, a CRISPR-Cas9-enabled Pfkp deletion recapitulated the metabolism of Camk4-/- Treg cells and improved their function and stability in vitro and in vivo. In SLE CD4+ T cells, PFKP enzymatic activity correlated with SLE disease activity and pharmacologic inhibition of CaMK4-normalized PFKP activity, leading to enhanced Treg cell function. In conclusion, we provide molecular insights in the defective metabolism and function of Treg cells in SLE and identify PFKP as a target to fine-tune Treg cell metabolism and thereby restore their function.
    DOI:  https://doi.org/10.1126/sciadv.adc9657
  4. Nat Commun. 2022 Nov 28. 13(1): 7338
    Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism.
    Claudio Bussi, Tiaan Heunis, Enrica Pellegrino, Elliott M Bernard, Nourdine Bah, Mariana Silva Dos Santos, Pierre Santucci, Beren Aylan, Angela Rodgers, Antony Fearns, Julia Mitschke, Christopher Moore, James I MacRae, Maria Greco, Thomas Reinheckel, Matthias Trost, Maximiliano G Gutierrez.
      Transient lysosomal damage after infection with cytosolic pathogens or silica crystals uptake results in protease leakage. Whether limited leakage of lysosomal contents into the cytosol affects the function of cytoplasmic organelles is unknown. Here, we show that sterile and non-sterile lysosomal damage triggers a cell death independent proteolytic remodelling of the mitochondrial proteome in macrophages. Mitochondrial metabolic reprogramming required leakage of lysosomal cathepsins and was independent of mitophagy, mitoproteases and proteasome degradation. In an in vivo mouse model of endomembrane damage, live lung macrophages that internalised crystals displayed impaired mitochondrial function. Single-cell RNA-sequencing revealed that lysosomal damage skewed metabolic and immune responses in alveolar macrophages subsets with increased lysosomal content. Functionally, drug modulation of macrophage metabolism impacted host responses to Mycobacterium tuberculosis infection in an endomembrane damage dependent way. This work uncovers an inter-organelle communication pathway, providing a general mechanism by which macrophages undergo mitochondrial metabolic reprograming after endomembrane damage.
    DOI:  https://doi.org/10.1038/s41467-022-34632-8
  5. Mol Cell. 2022 Dec 01. pii: S1097-2765(22)01067-X. [Epub ahead of print]82(23): 4407-4409
    D-2HG comes out of its shell: Metabolic effects on the immune environment.
    Juan Manuel Schvartzman, Andrew M Intlekofer.
      A recent study by Notarangelo et al.1 highlights the potential for tumor-derived D-2HG to inhibit neighboring T cell function through a novel mechanism.
    DOI:  https://doi.org/10.1016/j.molcel.2022.11.005
  6. Cell Rep. 2022 Nov 29. pii: S2211-1247(22)01622-9. [Epub ahead of print]41(9): 111744
    Inhibition of glutaminolysis restores mitochondrial function in senescent stem cells.
    Debanik Choudhury, Na Rong, Izuagie Ikhapoh, Nika Rajabian, Georgios Tseropoulos, Yulun Wu, Pihu Mehrotra, Ramkumar Thiyagarajan, Aref Shahini, Kenneth L Seldeen, Bruce R Troen, Pedro Lei, Stelios T Andreadis.
      Mitochondrial dysfunction, a hallmark of aging, has been associated with the onset of aging phenotypes and age-related diseases. Here, we report that impaired mitochondrial function is associated with increased glutamine catabolism in senescent human mesenchymal stem cells (MSCs) and myofibroblasts derived from patients suffering from Hutchinson-Gilford progeria syndrome. Increased glutaminase (GLS1) activity accompanied by loss of urea transporter SLC14A1 induces urea accumulation, mitochondrial dysfunction, and DNA damage. Conversely, blocking GLS1 activity restores mitochondrial function and leads to amelioration of aging hallmarks. Interestingly, GLS1 expression is regulated through the JNK pathway, as demonstrated by chemical and genetic inhibition. In agreement with our in vitro findings, tissues isolated from aged or progeria mice display increased urea accumulation and GLS1 activity, concomitant with declined mitochondrial function. Inhibition of glutaminolysis in progeria mice improves mitochondrial respiratory chain activity, suggesting that targeting glutaminolysis may be a promising strategy for restoring age-associated loss of mitochondrial function.
    Keywords:  CP: Cell biology; GLS1; Hutchinson-Gilford progeria syndrome; JNK; SLC14A1; aging; glutamine; mitochondria; senescence; urea
    DOI:  https://doi.org/10.1016/j.celrep.2022.111744
  7. Proc Natl Acad Sci U S A. 2022 Dec 06. 119(49): e2212548119
    Early microbial exposure shapes adult immunity by altering CD8+ T cell development.
    Cybelle Tabilas, David S Iu, Ciarán W P Daly, Kristel J Yee Mon, Arnold Reynaldi, Samantha P Wesnak, Jennifer K Grenier, Miles P Davenport, Norah L Smith, Andrew Grimson, Brian D Rudd.
      Microbial exposure during development can elicit long-lasting effects on the health of an individual. However, how microbial exposure in early life leads to permanent changes in the immune system is unknown. Here, we show that the microbial environment alters the set point for immune susceptibility by altering the developmental architecture of the CD8+ T cell compartment. In particular, early microbial exposure results in the preferential expansion of highly responsive fetal-derived CD8+ T cells that persist into adulthood and provide the host with enhanced immune protection against intracellular pathogens. Interestingly, microbial education of fetal-derived CD8+ T cells occurs during thymic development rather than in the periphery and involves the acquisition of a more effector-like epigenetic program. Collectively, our results provide a conceptual framework for understanding how microbial colonization in early life leads to lifelong changes in the immune system.
    Keywords:  CD8+ T cells; developmental layering; developmental origins of adult health and disease; immune training; pet-shop dirty mouse model
    DOI:  https://doi.org/10.1073/pnas.2212548119
  8. Food Funct. 2022 Nov 29.
    Dietary methionine restriction improves gut microbiota composition and prevents cognitive impairment in D-galactose-induced aging mice.
    Yuncong Xu, Yuhui Yang, Bowen Li, Yanli Xie, Yonghui Shi, Guowei Le.
      Dietary methionine restriction (MR) has been shown to delay aging and ameliorate age-related cognitive impairments. We hypothesized that changes in the gut microbiota may mediate these effects. To test this hypothesis, ICR mice subcutaneously injected with 150 mg kg-1 day-1D-galactose were fed a normal (0.86% methionine) or an MR (0.17% methionine) diet for 2 months. Multiple behavioral experiments were performed, and the gut microbiota composition, metabolite profiles related to short-chain fatty acids (SCFAs) in the feces, and indicators related to the redox and inflammatory states in the hippocampus were further analyzed. Our results indicated that MR alleviated cognitive impairment (including non-spatial memory deficits, working memory deficits, and hippocampus-dependent spatial memory deficits) and anxiety-like behavior in D-Gal-induced aging mice. Furthermore, MR increased the abundance of putative SCFA-producing bacteria such as Lachnospiraceae, Turicibacter, Roseburia, Ruminococcaceae_UCG-014, Intestinimonas, Rikenellaceae, Tyzzerella, and H2S-producing bacteria such as Desulfovibrio in feces. Moreover, MR reversed and normalized the levels of intestinal SCFAs (acetate, propionate, and butyrate) and important intermediate metabolites of the SCFAs (pyruvate, lactate, malate, fumarate, and succinate), abolished aging-induced oxidative stress and inflammatory responses, increased the levels of H2S in the plasma and hippocampus, and selectively modulated the expression of multiple learning- and memory-related genes in the hippocampus. These findings suggest that MR improved the gut microbiota composition and SCFA production and alleviated oxidative stress and inflammatory responses in the hippocampus, which might prevent cognitive impairment in D-galactose-induced aging mice.
    DOI:  https://doi.org/10.1039/d2fo03366f
  9. Sci Immunol. 2022 Dec 09. 7(78): eade5686
    IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein.
    Silvia Gaggero, Jonathan Martinez-Fabregas, Adeline Cozzani, Paul K Fyfe, Malo Leprohon, Jie Yang, F Emil Thomasen, Hauke Winkelmann, Romain Magnez, Alberto G Conti, Stephan Wilmes, Elizabeth Pohler, Manuel van Gijsel Bonnello, Xavier Thuru, Bruno Quesnel, Fabrice Soncin, Jacob Piehler, Kresten Lindorff-Larsen, Rahul Roychoudhuri, Ignacio Moraga, Suman Mitra.
      Cytokines interact with their receptors in the extracellular space to control immune responses. How the physicochemical properties of the extracellular space influence cytokine signaling is incompletely elucidated. Here, we show that the activity of interleukin-2 (IL-2), a cytokine critical to T cell immunity, is profoundly affected by pH, limiting IL-2 signaling within the acidic environment of tumors. Generation of lactic acid by tumors limits STAT5 activation, effector differentiation, and antitumor immunity by CD8+ T cells and renders high-dose IL-2 therapy poorly effective. Directed evolution enabled selection of a pH-selective IL-2 mutein (Switch-2). Switch-2 binds the IL-2 receptor subunit IL-2Rα with higher affinity, triggers STAT5 activation, and drives CD8+ T cell effector function more potently at acidic pH than at neutral pH. Consequently, high-dose Switch-2 therapy induces potent immune activation and tumor rejection with reduced on-target toxicity in normal tissues. Last, we show that sensitivity to pH is a generalizable property of a diverse range of cytokines with broad relevance to immunity and immunotherapy in healthy and diseased tissues.
    DOI:  https://doi.org/10.1126/sciimmunol.ade5686
  10. J Cancer Res Clin Oncol. 2022 Nov 29.
    Nutrient deprivation and hypoxia alter T cell immune checkpoint expression: potential impact for immunotherapy.
    Maria Davern, Noel E Donlon, Fiona O'Connell, Caoimhe Gaughan, Cillian O'Donovan, Jason McGrath, Andrew D Sheppard, Conall Hayes, Ross King, Hugo Temperley, Michael MacLean, Christine Bulter, Anshul Bhardwaj, Jenny Moore, Claire Donohoe, Narayanasamy Ravi, Melissa J Conroy, John V Reynolds, Joanne Lysaght.
       AIM: Use of immune checkpoint blockade to enhance T cell-mediated immunity within the hostile tumour microenvironment (TME) is an attractive approach in oesophageal adenocarcinoma (OAC). This study explored the effects of the hostile TME, including nutrient deprivation and hypoxia, on immune checkpoint (IC) expression and T cell phenotypes, and the potential use of nivolumab to enhance T cell function under such conditions.
    METHODS AND RESULTS: ICs were upregulated on stromal immune cells within the tumour including PD-L2, CTLA-4 and TIGIT. OAC patient-derived PBMCs co-cultured with OE33 OAC cells upregulated LAG-3 and downregulated the co-stimulatory marker CD27 on T cells, highlighting the direct immunosuppressive effects of tumour cells on T cells. Hypoxia and nutrient deprivation altered the secretome of OAC patient-derived PBMCs, which induced upregulation of PD-L1 and PD-L2 on OE33 OAC cells thus enhancing an immune-resistant phenotype. Importantly, culturing OAC patient-derived PBMCs under dual hypoxia and glucose deprivation, reflective of the conditions within the hostile TME, upregulated an array of ICs on the surface of T cells including PD-1, CTLA-4, A2aR, PD-L1 and PD-L2 and decreased expression of IFN-γ by T cells. Addition of nivolumab under these hostile conditions decreased the production of pro-tumorigenic cytokine IL-10.
    CONCLUSION: Collectively, these findings highlight the immunosuppressive crosstalk between tumour cells and T cells within the OAC TME. The ability of nivolumab to suppress pro-tumorigenic T cell phenotypes within the hostile TME supports a rationale for the use of immune checkpoint blockade to promote anti-tumour immunity in OAC. Study schematic: (A) IC expression profiles were assessed on CD45+ cells in peripheral whole blood and infiltrating tumour tissue from OAC patients in the treatment-naïve setting. (B) PBMCs were isolated from OAC patients and expanded ex vivo for 5 days using anti-CD3/28 + IL-2 T cell activation protocol and then co-cultured for 48 h with OE33 cells. T cell phenotypes were then assessed by flow cytometry. (C) PBMCs were isolated from OAC patients and expanded ex vivo for 5 days using anti-CD3/28 + IL-2 T cell activation protocol and then further cultured under conditions of nutrient deprivation or hypoxia for 48 h and T cell phenotypes were then assessed by flow cytometry.
    KEY FINDINGS: (A) TIGIT, CTLA-4 and PD-L2 were upregulated on CD45+ immune cells and CTLA-4 expression on CD45+ cells correlated with a subsequent decreased response to neoadjuvant regimen. (B) Following a 48 h co-culture with OE33 cells, T cells upregulated LAG-3 and decreased CD27 co-stimulatory marker. (C) Nutrient deprivation and hypoxia upregulated a range of ICs on T cells and decreased IFN-γ production by T cells. Nivolumab decreased IL-10 production by T cells under nutrient deprivation-hypoxic conditions.
    Keywords:  Glucose deprivation; Hypoxia; Immune checkpoints; Oesophageal adenocarcinoma; Tumour microenvironment
    DOI:  https://doi.org/10.1007/s00432-022-04440-0
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