bims-imseme 2020-11-08 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2020–11–08
27 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Mitochondria Synergize With P2 Receptors to Regulate Human T Cell Function.
Metabolic interventions: A new insight into the cancer immunotherapy.
Nr4a1 and Nr4a3 Reporter Mice Are Differentially Sensitive to T Cell Receptor Signal Strength and Duration.
Enhanced efficacy of simultaneous PD-1 and PD-L1 immune checkpoint blockade in high grade serous ovarian cancer.
Autophagy in T-cell differentiation, survival and memory.
Pyruvate Kinase Controls Signal Strength in the Insulin Secretory Pathway.
Origin and fine-tuning of effector CD8 T cell subpopulations in chronic infection.
Sex as a confounding factor in the effects of ageing on rat lymph node t cell compartment.
New Horizons: Novel Approaches to Enhance Healthspan Through Targeting Cellular Senescence and Related Aging Mechanisms.
Kras-Deficient T Cells Attenuate Graft-versus-Host Disease but Retain Graft-versus-Leukemia Activity.
T cell factor 1: A master regulator of the T cell response in disease.
Glucocorticoids in T cell development, differentiation and function.
A Blueprint for Characterizing Senescence.
A Tug-of-War Over Methionine.
CD4+ T Cell Profile and Activation Response in Sickle Cell Disease Patients with Osteonecrosis.
The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function.
Mitochondria Define Intestinal Stem Cell Differentiation Downstream of a FOXO/Notch Axis.
Transcriptional Memory-Like Imprints and Enhanced Functional Activity in γδ T Cells Following Resolution of Malaria Infection.
Regulatory (FoxP3+) T cells and TGF-β predict the response to anti-PD-1 immunotherapy in patients with non-small cell lung cancer.
Loss of metabolic plasticity underlies metformin toxicity in aged Caenorhabditis elegans.
PD-L1 degradation pathway and immunotherapy for cancer.
Anti-inflammatory and immune-modulatory impacts of berberine on activation of autoreactive T cells in autoimmune inflammation.
Central memory CD8+ T cells derive from stem-like Tcf7hi effector cells in the absence of cytotoxic differentiation.
Age-related loss of gene-to-gene transcriptional coordination among single cells.
PARP-1 activation after oxidative insult promotes energy stress-dependent phosphorylation of YAP1 and reduces cell viability.
Tissue-resident CD8+ T cells drive age-associated chronic lung sequelae after viral pneumonia.
The Roles of Mitochondrial Folate Metabolism in Supporting Mitochondrial DNA Synthesis, Oxidative Phosphorylation, and Cellular Function.

Front Immunol. 2020 ;11 549889

Mitochondria Synergize With P2 Receptors to Regulate Human T Cell Function.

Carola Ledderose, Wolfgang G Junger.

  Intracellular ATP is the universal energy carrier that fuels many cellular processes. However, immune cells can also release a portion of their ATP into the extracellular space. There, ATP activates purinergic receptors that mediate autocrine and paracrine signaling events needed for the initiation, modulation, and termination of cell functions. Mitochondria contribute to these processes by producing ATP that is released. Here, we summarize the synergistic interplay between mitochondria and purinergic signaling that regulates T cell functions. Specifically, we discuss how mitochondria interact with P2X1, P2X4, and P2Y11 receptors to regulate T cell metabolism, cell migration, and antigen recognition. These mitochondrial and purinergic signaling mechanisms are indispensable for host immune defense. However, they also represent an Achilles heel that can render the host susceptible to infections and inflammatory disorders. Hypoxia and mitochondrial dysfunction deflate the purinergic signaling mechanisms that regulate T cells, while inflammation and tissue damage generate excessive systemic ATP levels that distort autocrine purinergic signaling and impair T cell function. An improved understanding of the metabolic and purinergic signaling mechanisms that regulate T cells may lead to novel strategies for the diagnosis and treatment of infectious and inflammatory diseases.

Keywords:  P2X1; P2X4; P2Y11; inflammation; mitochondria

DOI:  https://doi.org/10.3389/fimmu.2020.549889
Arch Biochem Biophys. 2020 Oct 31. pii: S0003-9861(20)30668-8. [Epub ahead of print] 108659

Metabolic interventions: A new insight into the cancer immunotherapy.

Tao Yu, Tianhan Dong, Haniyeh Eyvani, Yuanzhang Fang, Xiyu Wang, Xinna Zhang, Xiongbin Lu.

  Metabolic reprogramming confers cancer cells plasticity and viability under harsh conditions. Such active alterations lead to cell metabolic dependency, which can be exploited as an attractive target in development of effective antitumor therapies. Similar to cancer cells, activated T cells also execute global metabolic reprogramming for their proliferation and effector functions when recruited to the tumor microenvironment (TME). However, the high metabolic activity of rapidly proliferating cancer cells can compete for nutrients with immune cells in the TME, and consequently, suppressing their anti-tumor functions. Thus, therapeutic strategies could aim to restore T cell metabolism and anti-tumor responses in TME by targeting the metabolic dependence of cancer cells. In this review, we highlight current research progress on metabolic reprogramming and the interplay between cancer cells and immune cells. We also discuss potential therapeutic intervention strategies for targeting metabolic pathways to improve tumor immunotherapy efficacy.

Keywords:  Metabolic reprogramming; Nutrients competing; Tumor microenvironment; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.abb.2020.108659
Cell Rep. 2020 Nov 03. pii: S2211-1247(20)31317-6. [Epub ahead of print]33(5): 108328

Nr4a1 and Nr4a3 Reporter Mice Are Differentially Sensitive to T Cell Receptor Signal Strength and Duration.

Emma Jennings, Thomas A E Elliot, Natasha Thawait, Shivani Kanabar, Juan Carlos Yam-Puc, Masahiro Ono, Kai-Michael Toellner, David C Wraith, Graham Anderson, David Bending.

  Nr4a receptors are activated by T cell receptor (TCR) signaling and play key roles in T cell differentiation. Which TCR signaling pathways regulate Nr4a receptors and their sensitivities to TCR signal strength and duration remains unclear. Using Nr4a1/Nur77-GFP and Nr4a3-Timer of cell kinetics and activity (Tocky) mice, we elucidate the signaling pathways governing Nr4a receptor expression. We reveal that Nr4a1-Nr4a3 are Src family kinase dependent. Moreover, Nr4a2 and Nr4a3 are attenuated by calcineurin inhibitors and bind nuclear factor of activated T cells 1 (NFAT1), highlighting a necessary and sufficient role for NFAT1 in the control of Nr4a2 and Nr4a3, but redundancy for Nr4a1. Nr4a1-GFP is activated by tonic and cognate signals during T cell development, whereas Nr4a3-Tocky requires cognate peptide:major histocompatibility complex (MHC) interactions for expression. Compared to Nr4a3-Tocky, Nr4a1-GFP is approximately 2- to 3-fold more sensitive to TCR signaling and is detectable by shorter periods of TCR signaling. These findings suggest that TCR signal duration may be an underappreciated aspect influencing the developmental fate of T cells in vivo.

Keywords:  NFAT; Nr4a1-GFP; Nr4a3-Tocky; T cell activation; T cell development; T cell receptor signaling

DOI:  https://doi.org/10.1016/j.celrep.2020.108328
Cancer Res. 2020 Nov 06. pii: canres.1674.2020. [Epub ahead of print]

Enhanced efficacy of simultaneous PD-1 and PD-L1 immune checkpoint blockade in high grade serous ovarian cancer.

Changxin Wan, Matthew P Keany, Han Dong, Linah F Al-Alem, Unnati M Pandya, Suzan Lazo, Karsten Boehnke, Katherine N Lynch, Rui Xu, Dominique T Zarrella, Shengqing Gu, Paloma Cejas, Klothilda Lim, Henry W Long, Kevin M Elias, Neil S Horowitz, Colleen M Feltmate, Michael G Muto, Michael J Worley, Ross S Berkowitz, Ursula A Matulonis, Marisa R Nucci, Christopher P Crum, Bo R Rueda, Myles Brown, Xiaole Shirley Liu, Sarah J Hill.

Immune therapies have had limited efficacy in high grade serous ovarian cancer (HGSC), as the cellular targets and mechanism(s) of action of these agents in HGSC are unknown. Here we performed immune functional and single cell RNA-seq transcriptional profiling on novel HGSC organoid/immune cell co-cultures treated with a unique bispecific anti-PD-1/PD-L1 antibody compared to monospecific anti-PD-1 or anti-PD-L1 controls. Comparing the functions of these agents across all immune cell types in real time identified key immune checkpoint blockade (ICB) targets that have eluded currently available monospecific therapies. The bispecific antibody induced superior cellular state changes in both T and NK cells. It uniquely induced NK cells to transition from inert to more active and cytotoxic phenotypes, implicating NK cells as a key missing component of the current ICB-induced immune response in HGSC. It also induced a subset of CD8 T cells to transition from naïve to more active and cytotoxic progenitor-exhausted phenotypes post-treatment, revealing the small, previously uncharacterized population of CD8 T cells responding to ICB in HGSC. These state changes were driven partially through bispecific antibody-induced downregulation of the bromodomain-containing protein BRD1. Small molecule inhibition of BRD1 induced similar state changes in vitro and demonstrated efficacy in vivo, validating the co-culture results. Our results demonstrate that state changes in both NK and a subset of T cells may be critical in inducing an effective anti-tumor immune response and suggest that immune therapies able to induce such cellular state changes, such as BRD1 inhibitors, may have increased efficacy in HGSC.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-1674
Immunol Cell Biol. 2020 Nov 03.

Autophagy in T-cell differentiation, survival and memory.

Liqing Wang, Jugal Kishore Das, Anil Kumar, Hao-Yun Peng, Yijie Ren, Xiaofang Xiong, Jin-Ming Yang, Jianxun Song.

  Over the past decade, autophagy has emerged as a critical regulatory mechanism of the immune system through critically controlling various aspects of T cell biology and determining the fate of different T cell subsets. Autophagy maintains T cell development and survival via regulating the degradation of organelles and apoptotic proteins. The autophagic process also impacts the formation of memory T cells. Alteration of autophagy in T cells may lead to a variety of pathological conditions such as inflammation, autoimmune diseases, and cancer. In this review, we discuss how autophagy impacts T cell differentiation, survival, and memory, and its implication in immunotherapy for various diseases.

Keywords:  Autophagy; T cells; differentiation; immunotherapy; memory; survival

DOI:  https://doi.org/10.1111/imcb.12422
Cell Metab. 2020 Nov 03. pii: S1550-4131(20)30540-4. [Epub ahead of print]32(5): 736-750.e5

Pyruvate Kinase Controls Signal Strength in the Insulin Secretory Pathway.

Sophie L Lewandowski, Rebecca L Cardone, Hannah R Foster, Thuong Ho, Evgeniy Potapenko, Chetan Poudel, Halena R VanDeusen, Sophia M Sdao, Tiago C Alves, Xiaojian Zhao, Megan E Capozzi, Arnaldo H de Souza, Ishrat Jahan, Craig J Thomas, Craig S Nunemaker, Dawn Belt Davis, Jonathan E Campbell, Richard G Kibbey, Matthew J Merrins.

  Pancreatic β cells couple nutrient metabolism with appropriate insulin secretion. Here, we show that pyruvate kinase (PK), which converts ADP and phosphoenolpyruvate (PEP) into ATP and pyruvate, underlies β cell sensing of both glycolytic and mitochondrial fuels. Plasma membrane-localized PK is sufficient to close KATP channels and initiate calcium influx. Small-molecule PK activators increase the frequency of ATP/ADP and calcium oscillations and potently amplify insulin secretion. PK restricts respiration by cyclically depriving mitochondria of ADP, which accelerates PEP cycling until membrane depolarization restores ADP and oxidative phosphorylation. Our findings support a compartmentalized model of β cell metabolism in which PK locally generates the ATP/ADP required for insulin secretion. Oscillatory PK activity allows mitochondria to perform synthetic and oxidative functions without any net impact on glucose oxidation. These findings suggest a potential therapeutic route for diabetes based on PK activation that would not be predicted by the current consensus single-state model of β cell function.

Keywords:  K(ATP) channel; anaplerosis; biosensor imaging; insulin secretion; metabolic flux; metabolic oscillations; oxidative phosphorylation; phosphoenolpyruvate cycle; pyruvate kinase; β cell metabolism

DOI:  https://doi.org/10.1016/j.cmet.2020.10.007
Curr Opin Virol. 2020 Oct 30. pii: S1879-6257(20)30100-0. [Epub ahead of print]46 27-35

Origin and fine-tuning of effector CD8 T cell subpopulations in chronic infection.

Kristiyan Kanev, Dietmar Zehn.

Persisting stimulation can skew CD8 T cells towards a hypofunctional state commonly referred to as T cell exhaustion. This functional attenuation likely constitutes a mechanism which evolved to balance T cell mediated viral control versus overwhelming immunopathology. Here, we highlight the recent progress in defining the genetic mechanisms and factors shaping the differentiation of exhausted CD8 T cells. We review how the transcription factor Tox imposes an exhausted phenotype in the Tcf1+ progenitors and how CD4 help fine-tunes the effector subsets that emerge from this progenitor population. Both processes critically shape the spectrum of effector function performed by CD8 T cells and the level of resulting virus control. Finally, we discuss how these insights can be exploited to boost the immune response in chronic infection and cancer.

DOI: https://doi.org/10.1016/j.coviro.2020.10.003
Exp Gerontol. 2020 Oct 28. pii: S0531-5565(20)30488-5. [Epub ahead of print] 111140

Sex as a confounding factor in the effects of ageing on rat lymph node t cell compartment.

Mirjana Nacka-Aleksić, Zorica Stojić-Vukanić, Ivan Pilipović, Veljko Blagojević, Jelena Kotur-Stevuljević, Gordana Leposavić.

  The study examined the influence of sex on the alterations occurring with ageing in rat lymph node (LN) T cell compartment. In female and male rats the decrease in LN T cell counts was followed by a shift in CD4+/CD8+ T cell ratio towards CD8+ T cells, which was more prominent in males than in females. With ageing, in both major LN T cell subpopulations naïve (recent thymic emigrants and mature naïve cells) to memory/activated T cell ratio shifted to the side of memory/activated cells in female, and particularly in male rats. The frequency of regulatory CD25 + Foxp3+ cells increased among LN CD4+/CD8+ T cells with ageing, reflecting, at least partly, an enhanced conversion of effector T cells into regulatory cells. This was also more prominent in male rats. The more prounounced increase in LN oxidative damage and the expression levels of proinflammatory cytokines in male rats with ageing, most likely contributed to the greater frequency of proinflammatory, replicatively senescent CD28- cells expressing CD11b (innate cell marker), among T cells of old male rats compared with age-matched females. The increase in LN oxidation/proinflammatory state with ageing was also consistent with the accumulation of exhausted PD-1high cells among T lymphocytes, particularly prominent among CD8+ T cells from male rats. Finally, by calculating a summary score for the key ageing-relevant parameters (an ageing index), a faster development of the deleterious changes in the T cell compartment occurring with ageing was confirmed in male rat LNs. Additionally, the study pointed to indices of LN T cell compartment ageing which correlate with those in peripheral blood.

Keywords:  Ageing; Exhausted T cells; Lymph node T cells; Replicatively senescent T cells; Sex differences

DOI:  https://doi.org/10.1016/j.exger.2020.111140
J Clin Endocrinol Metab. 2020 Nov 06. pii: dgaa728. [Epub ahead of print]

New Horizons: Novel Approaches to Enhance Healthspan Through Targeting Cellular Senescence and Related Aging Mechanisms.

Tamar Tchkonia, Allyson K Palmer, James L Kirkland.

  The elderly population is increasing faster than other segments of the population throughout the world. Age is the leading predictor for most chronic diseases and disorders, multimorbidity, geriatric syndromes, and impaired ability to recover from accidents or illnesses. Enhancing the duration of health and independence, termed healthspan, would be more desirable than extending lifespan merely by prolonging the period of morbidity toward the end of life. The geroscience hypothesis posits that healthspan can be extended by targeting fundamental aging mechanisms, rather than attempting to address each age-related disease one at a time, only so the afflicted individual survives disabled and dies shortly afterward of another age-related disease. These fundamental aging mechanisms include, among others, chronic inflammation, fibrosis, stem cell/ progenitor dysfunction, DNA damage, epigenetic changes, metabolic shifts, destructive metabolite generation, mitochondrial dysfunction, misfolded or aggregated protein accumulation, and cellular senescence. These processes appear to be tightly interlinked, as targeting any one appears to affect many of the rest, underlying our Unitary Theory of Fundamental Aging Mechanisms. Interventions targeting many fundamental aging processes are being developed, including dietary manipulations, metformin, mTOR (mechanistic target of rapamycin) inhibitors, and senolytics, which are in early human trials. These interventions could lead to greater healthspan benefits than treating age-related diseases one at a time. To illustrate these points, we focus on cellular senescence and therapies in development to target senescent cells. Combining interventions targeting aging mechanisms with disease-specific drugs could result in more than additive benefits for currently difficult-to-treat or intractable diseases. More research attention needs to be devoted to targeting fundamental aging processes.

Keywords:   senolytics; SASP (senescence-associated secretory phenotype); geroscience hypothesis; healthspan; multimorbidity; unitary theory of fundamental aging mechanisms

DOI:  https://doi.org/10.1210/clinem/dgaa728
J Immunol. 2020 Nov 06. pii: ji2000006. [Epub ahead of print]

Kras-Deficient T Cells Attenuate Graft-versus-Host Disease but Retain Graft-versus-Leukemia Activity.

Lan Luo, Yuhong Chen, Xiao Chen, Yongwei Zheng, Vivian Zhou, Mei Yu, Robert Burns, Wen Zhu, Guoping Fu, Juan C Felix, Christopher Hartley, Alisa Damnernsawad, Jing Zhang, Renren Wen, Williams R Drobyski, Chunji Gao, Demin Wang.

Acute graft-versus-host disease (aGVHD) is one major serious complication that is induced by alloreactive donor T cells recognizing host Ags and limits the success of allogeneic hematopoietic stem cell transplantation. In the current studies, we identified a critical role of Kras in regulating alloreactive T cell function during aGVHD. Kras deletion in donor T cells dramatically reduced aGVHD mortality and severity in an MHC-mismatched allogeneic hematopoietic stem cell transplantation mouse model but largely maintained the antitumor capacity. Kras-deficient CD4 and CD8 T cells exhibited impaired TCR-induced activation of the ERK pathway. Kras deficiency altered TCR-induced gene expression profiles, including the reduced expression of various inflammatory cytokines and chemokines. Moreover, Kras deficiency inhibited IL-6-mediated Th17 cell differentiation and impaired IL-6-induced ERK activation and gene expression in CD4 T cells. These findings support Kras as a novel and effective therapeutic target for aGVHD.

DOI: https://doi.org/10.4049/jimmunol.2000006
Sci Immunol. 2020 Nov 06. pii: eabb9726. [Epub ahead of print]5(53):

T cell factor 1: A master regulator of the T cell response in disease.

Giulia Escobar, Davide Mangani, Ana C Anderson.

Recent advances have redefined a role for T cell factor 1 (TCF1) that goes beyond T cell development and T memory formation and encompasses new functions in the regulation of T cell biology. Here, we discuss the multifaceted and context-dependent role of TCF1 in peripheral T cells, particularly during disease-induced inflammatory states such as autoimmunity, cancer, and chronic infections. Understanding how TCF1 fine-tunes peripheral T cell biology holds the potential to tailor improved immune-targeted therapies.

DOI: https://doi.org/10.1126/sciimmunol.abb9726
Nat Rev Immunol. 2020 Nov 04.

Glucocorticoids in T cell development, differentiation and function.

Matthew D Taves, Jonathan D Ashwell.

Glucocorticoids (GCs) are small lipid hormones produced by the adrenals that maintain organismal homeostasis. Circadian and stress-induced changes in systemic GC levels regulate metabolism, cardiovascular and neural function, reproduction and immune activity. Our understanding of GC effects on immunity comes largely from administration of exogenous GCs to treat immune or inflammatory disorders. However, it is increasingly clear that endogenous GCs both promote and suppress T cell immunity. Examples include selecting an appropriate repertoire of T cell receptor (TCR) self-affinities in the thymus, regulating T cell trafficking between anatomical compartments, suppressing type 1 T helper (TH1) cell responses while permitting TH2 cell and, especially, IL-17-producing T helper cell responses, and promoting memory T cell differentiation and maintenance. Furthermore, in addition to functioning at a distance, extra-adrenal (local) production allows GCs to act as paracrine signals, specifically targeting activated T cells in various contexts in the thymus, mucosa and tumours. These pleiotropic effects on different T cell populations during development and immune responses provide a nuanced understanding of how GCs shape immunity.

DOI: https://doi.org/10.1038/s41577-020-00464-0
Cell. 2020 Oct 29. pii: S0092-8674(20)31396-9. [Epub ahead of print]

A Blueprint for Characterizing Senescence.

Ananda L Roy, Felipe Sierra, Kevin Howcroft, Dinah S Singer, Norman Sharpless, Richard J Hodes, Elizabeth L Wilder, James M Anderson.

Given the heterogeneity of senescent cells, our knowledge of both the drivers and consequences of cellular senescence in tissues and organs remains limited, as is our understanding of how this process could be harnessed for human health. Here we identified five broad areas that would help propel the field forward.

DOI: https://doi.org/10.1016/j.cell.2020.10.032
Cell Metab. 2020 Nov 03. pii: S1550-4131(20)30549-0. [Epub ahead of print]32(5): 699-701

A Tug-of-War Over Methionine.

Ke Xu, Amy Shyu, Ming O Li.

Nutrient acquisition and metabolism are integral components of cell growth, proliferation, and differentiation programs. In a recent study in Nature, Bian et al. (2020) revealed that cancer cells outcompete T cells for methionine uptake, resulting in diminished SAM production, attenuated H3K79 dimethylation, decreased STAT5 expression, and impaired T cell immunity to cancer.

DOI: https://doi.org/10.1016/j.cmet.2020.10.016
Mediators Inflamm. 2020 ;2020 1747894

CD4+ T Cell Profile and Activation Response in Sickle Cell Disease Patients with Osteonecrosis.

Paula B Daltro, Tiago O Ribeiro, Gildásio C Daltro, Roberto J Meyer, Vitor Fortuna.

Recent evidence suggests that abnormalities involving CD4+T lymphocytes are associated with the pathophysiology of osteonecrosis (ON); however, few studies have addressed the CD4+T cells in ON related to sickle cell disease (SCD/ON). In addition, T cells producing multiple cytokines simultaneously are often present in the inflammatory milieu and may be implicated in the immune response observed in SCD/ON. In the present study, we aimed to characterize the functional status of CD4+T cells in SCD by simultaneously determining the frequency of IFN-γ +, IL-4+, and IL-17+ CD4+T in cell cultures under exogenous stimuli. Peripheral blood mononuclear cells (PB-MNCs) from 9 steady-state SCD patients, 15 SCD/ON patients, and 19 healthy controls had functional status of CD4+T cells analyzed. Bone marrow mononuclear cells (BM-MNCs) from 24 SCD/ON patients (SCD BM) and 18 patients with ON not related to SCD (non-SCD BM) were also analyzed. We found that PB-MNC of SCD patients with or without ON presented significantly reduced TCD4+, TCD8+, and TCD4+ naïve cell frequencies and increased frequency of circulating CD4+T cells able to simultaneously produce IFN-γ +/IL4+ and IL-17+/IL4+ compared to healthy controls. Conversely, the polyclonal stimulation of BM-MNC induced an increased frequency of CD4+IFN-γ + and CD4+IL-17+ in SCD BM compared to non-SCD BM. The increased proportion of CD4+ T cells able to produce a broad spectrum of proinflammatory cytokines after a strong stimulus indicates that the immune system in SCD/ON patients presents an expressive pool of partially differentiated cells ready to take on effector function. It is possible that this increased subpopulation may extend to inflammatory sites of target organs and may contribute to the maintenance of inflammation and the pathophysiology of osteonecrosis in sickle cell disease.

DOI: https://doi.org/10.1155/2020/1747894
J Exp Med. 2021 Mar 01. pii: e20200829. [Epub ahead of print]218(3):

The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function.

Christopher Mapperley, Louie N van de Lagemaat, Hannah Lawson, Andrea Tavosanis, Jasmin Paris, Joana Campos, David Wotherspoon, Jozef Durko, Annika Sarapuu, Junho Choe, Ivayla Ivanova, Daniela S Krause, Alex von Kriegsheim, Christian Much, Marcos Morgan, Richard I Gregory, Adam J Mead, Dónal O'Carroll, Kamil R Kranc.

The mRNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation of the m6A mRNA reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion and compromises acute myeloid leukemia. Here we investigate the long-term impact of YTHDF2 deletion on HSC maintenance and multilineage hematopoiesis. We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial transplantation, display increased abundance of multiple m6A-modified inflammation-related transcripts, and chronically activate proinflammatory pathways. Consistent with the detrimental consequences of chronic activation of inflammatory pathways in HSCs, hematopoiesis-specific Ythdf2 deficiency results in a progressive myeloid bias, loss of lymphoid potential, HSC expansion, and failure of aged Ythdf2-deficient HSCs to reconstitute multilineage hematopoiesis. Experimentally induced inflammation increases YTHDF2 expression, and YTHDF2 is required to protect HSCs from this insult. Thus, our study positions YTHDF2 as a repressor of inflammatory pathways in HSCs and highlights the significance of m6A in long-term HSC maintenance.

DOI: https://doi.org/10.1084/jem.20200829
Cell Metab. 2020 Nov 03. pii: S1550-4131(20)30538-6. [Epub ahead of print]32(5): 889-900.e7

Mitochondria Define Intestinal Stem Cell Differentiation Downstream of a FOXO/Notch Axis.

Marlies C Ludikhuize, Maaike Meerlo, Marc Pages Gallego, Despina Xanthakis, Mar Burgaya Julià, Nguyen T B Nguyen, Eline C Brombacher, Nalan Liv, Madelon M Maurice, Ji-Hye Paik, Boudewijn M T Burgering, Maria J Rodriguez Colman.

  Differential WNT and Notch signaling regulates differentiation of Lgr5+ crypt-based columnar cells (CBCs) into intestinal cell lineages. Recently we showed that mitochondrial activity supports CBCs, while adjacent Paneth cells (PCs) show reduced mitochondrial activity. This implies that CBC differentiation into PCs involves a metabolic transition toward downregulation of mitochondrial dependency. Here we show that Forkhead box O (FoxO) transcription factors and Notch signaling interact in determining CBC fate. In agreement with the organoid data, Foxo1/3/4 deletion in mouse intestine induces secretory cell differentiation. Importantly, we show that FOXO and Notch signaling converge on regulation of mitochondrial fission, which in turn provokes stem cell differentiation into goblet cells and PCs. Finally, scRNA-seq-based reconstruction of CBC differentiation trajectories supports the role of FOXO, Notch, and mitochondria in secretory differentiation. Together, this points at a new signaling-metabolic axis in CBC differentiation and highlights the importance of mitochondria in determining stem cell fate.

Keywords:  FOXO; Notch; differentiation; intestine; metabolism; mitochondria; stem cells

DOI:  https://doi.org/10.1016/j.cmet.2020.10.005
Front Immunol. 2020 ;11 582358

Transcriptional Memory-Like Imprints and Enhanced Functional Activity in γδ T Cells Following Resolution of Malaria Infection.

Rasika Kumarasingha, Lisa J Ioannidis, Waruni Abeysekera, Stephanie Studniberg, Dinidu Wijesurendra, Ramin Mazhari, Daniel P Poole, Ivo Mueller, Louis Schofield, Diana S Hansen, Emily M Eriksson.

  γδ T cells play an essential role in the immune response to many pathogens, including Plasmodium. However, long-lasting effects of infection on the γδ T cell population still remain inadequately understood. This study focused on assessing molecular and functional changes that persist in the γδ T cell population following resolution of malaria infection. We investigated transcriptional changes and memory-like functional capacity of malaria pre-exposed γδ T cells using a Plasmodium chabaudi infection model. We show that multiple genes associated with effector function (chemokines, cytokines and cytotoxicity) and antigen-presentation were upregulated in P. chabaudi-exposed γδ T cells compared to γδ T cells from naïve mice. This transcriptional profile was positively correlated with profiles observed in conventional memory CD8+ T cells and was accompanied by enhanced reactivation upon secondary encounter with Plasmodium-infected red blood cells in vitro. Collectively our data demonstrate that Plasmodium exposure result in "memory-like imprints" in the γδ T cell population and also promotes γδ T cells that can support antigen-presentation during subsequent infections.

Keywords:  Plasmodium; RNA-Seq; chabaudi; memory; γδ T cell

DOI:  https://doi.org/10.3389/fimmu.2020.582358
Sci Rep. 2020 Nov 04. 10(1): 18994

Regulatory (FoxP3+) T cells and TGF-β predict the response to anti-PD-1 immunotherapy in patients with non-small cell lung cancer.

Jiae Koh, Joon Young Hur, Kyoung Young Lee, Mi Soon Kim, Jae Yeong Heo, Bo Mi Ku, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn.

Antitumor immune responses induced by immune checkpoint inhibitors anti-PD-1 or anti-PD-L1 have been used as therapeutic strategies in advanced non-small cell lung cancer (NSCLC) patients over the last decade. Favorable antitumor activity to immune checkpoint inhibitors is correlated with high PD-L1 expression, increased tumor-infiltrating lymphocytes, and decreased suppressive immune cells including Treg cells, myeloid-derived suppressor cells, or tumor-associated macrophages in various cancer types. In this study, we investigated the potential correlation between clinical outcomes and peripheral blood immune cell profiles, specifically focused on FoxP3+ Treg cells, collected at baseline and one week after anti-PD-1 therapy in two independent cohorts of patients with NSCLC: a discovery cohort of 83 patients and a validation cohort of 49 patients. High frequencies of circulating Treg cells one week after anti-PD-1 therapy were correlated with a high response rate, longer progression-free survival, and overall survival. Furthermore, high levels of TGF-β and Treg cells were associated with favorable clinical outcomes. Our results suggest that higher levels of FoxP3+ Treg cells and TGF-β can predict a favorable response to anti-PD-1 immunotherapy in patients with advanced NSCLC.

DOI: https://doi.org/10.1038/s41598-020-76130-1
Nat Metab. 2020 Nov 02.

Loss of metabolic plasticity underlies metformin toxicity in aged Caenorhabditis elegans.

Lilia Espada, Alexander Dakhovnik, Prerana Chaudhari, Asya Martirosyan, Laura Miek, Tetiana Poliezhaieva, Yvonne Schaub, Ashish Nair, Nadia Döring, Norman Rahnis, Oliver Werz, Andreas Koeberle, Joanna Kirkpatrick, Alessandro Ori, Maria A Ermolaeva.

Current clinical trials are testing the life-extending benefits of the diabetes drug metformin in healthy individuals without diabetes. However, the metabolic response of a non-diabetic cohort to metformin treatment has not been studied. Here, we show in C. elegans and human primary cells that metformin shortens lifespan when provided in late life, contrary to its positive effects in young organisms. We find that metformin exacerbates ageing-associated mitochondrial dysfunction, causing respiratory failure. Age-related failure to induce glycolysis and activate the dietary-restriction-like mobilization of lipid reserves in response to metformin result in lethal ATP exhaustion in metformin-treated aged worms and late-passage human cells, which can be rescued by ectopic stabilization of cellular ATP content. Metformin toxicity is alleviated in worms harbouring disruptions in insulin-receptor signalling, which show enhanced resilience to mitochondrial distortions at old age. Together, our data show that metformin induces deleterious changes of conserved metabolic pathways in late life, which could bring into question its benefits for older individuals without diabetes.

DOI: https://doi.org/10.1038/s42255-020-00307-1
Cell Death Dis. 2020 Nov 06. 11(11): 955

PD-L1 degradation pathway and immunotherapy for cancer.

Qian Gou, Chen Dong, Huihui Xu, Bibimaryam Khan, Jianhua Jin, Qian Liu, Juanjuan Shi, Yongzhong Hou.

Programmed death ligand 1 (PD-L1, CD274) is an essential immune checkpoint protein that binds to programmed death 1 (PD-1) on T-lymphocytes. T cell plays a critical role in killing cancer cells while the cancer cell exhibits immune escape by the expression of PD-L1. The binding of PD-L1 to PD-1 inhibits T cell proliferation and activity, leading to tumor immunosuppression. Increasing evidence shows that PD-L1 protein undergoes degradation in proteasomes or lysosomes by multiple pathways, leading to enhanced immunotherapy for cancer. Although some specific drugs induce PD-L1 degradation and increase antitumor activity, the combination of these drugs with PD-L1/PD-1 blockade significantly enhances cancer immunotherapy. In this review, we have discussed the interaction of PD-L1 degradation with cancer immunotherapy.

DOI: https://doi.org/10.1038/s41419-020-03140-2
J Cell Mol Med. 2020 Nov 01.

Anti-inflammatory and immune-modulatory impacts of berberine on activation of autoreactive T cells in autoimmune inflammation.

Seyed-Morteza Ehteshamfar, Masoume Akhbari, Jalil Tavakol Afshari, Motahareh Seyedi, Banafsheh Nikfar, Abbas Shapouri-Moghaddam, Erfan Ghanbarzadeh, Amir Abbas Momtazi-Borojeni.

  Autoreactive inflammatory CD4+ T cells, such as T helper (Th)1 and Th17 subtypes, have been found to associate with the pathogenesis of autoimmune disorders. On the other hand, CD4+ Foxp3+ T regulatory (Treg) cells are crucial for the immune tolerance and have a critical role in the suppression of the excessive immune and inflammatory response promoted by these Th cells. In contrast, dendritic cells (DCs) and macrophages are immune cells that through their inflammatory functions promote autoreactive T-cell responses in autoimmune conditions. In recent years, there has been increasing attention to exploring effective immunomodulatory or anti-inflammatory agents from the herbal collection of traditional medicine. Berberine, an isoquinoline alkaloid, is one of the main active ingredients extracted from medicinal herbs and has been shown to exert various biological and pharmacological effects that are suggested to be mainly attributed to its anti-inflammatory and immunomodulatory properties. Several lines of experimental study have recently investigated the therapeutic potential of berberine for treating autoimmune conditions in animal models of human autoimmune diseases. Here, we aimed to seek mechanisms underlying immunomodulatory and anti-inflammatory effects of berberine on autoreactive inflammatory responses in autoimmune conditions. Reported data reveal that berberine can directly suppress functions and differentiation of pro-inflammatory Th1 and Th17 cells, and indirectly decrease Th cell-mediated inflammation through modulating or suppressing other cells assisting autoreactive inflammation, such as Tregs, DCs and macrophages.

Keywords:  T helper cell; autoimmunity; berberine; dendritic cell; inflammation; macrophage

DOI:  https://doi.org/10.1111/jcmm.16049
Immunity. 2020 Oct 23. pii: S1074-7613(20)30399-X. [Epub ahead of print]

Central memory CD8+ T cells derive from stem-like Tcf7hi effector cells in the absence of cytotoxic differentiation.

Daniela Pais Ferreira, Joana Gomes Silva, Tania Wyss, Silvia A Fuertes Marraco, Léonardo Scarpellino, Mélanie Charmoy, Roeltje Maas, Imran Siddiqui, Li Tang, Johanna A Joyce, Mauro Delorenzi, Sanjiv A Luther, Daniel E Speiser, Werner Held.

  Central memory CD8+ T cells (Tcm) control systemic secondary infections and can protect from chronic infection and cancer as a result of their stem-cell-like capacity to expand, differentiate, and self-renew. Central memory is generally thought to emerge following pathogen clearance and to form based on the de-differentiation of cytolytic effector cells. Here, we uncovered rare effector-phase CD8+ T cells expressing high amounts of the transcription factor Tcf7 (Tcf1) that showed no evidence of prior cytolytic differentiation and that displayed key hallmarks of Tcm cells. These effector-phase Tcf7hi cells quantitatively yielded Tcm cells based on lineage tracing. Mechanistically, Tcf1 counteracted the differentiation of Tcf7hi cells and sustained the expression of conserved adult stem-cell genes that were critical for CD8+ T cell stemness. The discovery of stem-cell-like CD8+ T cells during the effector response to acute infection provides an opportunity to optimize Tcm cell formation by vaccination.

Keywords:  CD8(+) T cells; Granzyme; LCMV infection; T cell factor 1 (Tcf1) (Tcf7); central memory; effector differentiation; stemness; vaccination

DOI:  https://doi.org/10.1016/j.immuni.2020.09.005
Nat Metab. 2020 Nov 02.

Age-related loss of gene-to-gene transcriptional coordination among single cells.

Orr Levy, Guy Amit, Dana Vaknin, Tom Snir, Sol Efroni, Peter Castaldi, Yang-Yu Liu, Haim Y Cohen, Amir Bashan.

A long-standing model holds that stochastic aberrations of transcriptional regulation play a key role in the process of ageing. While transcriptional dysregulation is observed in many cell types in the form of increased cell-to-cell variability, its generality to all cell types remains doubted. Here, we propose a new approach for analysing transcriptional regulation in single-cell RNA sequencing data by focusing on the global coordination between the genes rather than the variability of individual genes or correlations between pairs of genes. Consistently, across very different organisms and cell types, we find a decrease in the gene-to-gene transcriptional coordination in ageing cells. In addition, we find that loss of gene-to-gene transcriptional coordination is associated with high mutational load of a specific, age-related signature and with radiation-induced DNA damage. These observations suggest a general, potentially universal, stochastic attribute of transcriptional dysregulation in ageing.

DOI: https://doi.org/10.1038/s42255-020-00304-4
Biochem J. 2020 Nov 04. pii: BCJ20200525. [Epub ahead of print]

PARP-1 activation after oxidative insult promotes energy stress-dependent phosphorylation of YAP1 and reduces cell viability.

Sandra Maria Martín Guerrero, Pedro Casado, Maruan Hijazi, Vinothini Rajeeve, Julio Plaza, Francisco Abadía-Molina, Julio Navascués, Miguel A Cuadros, Pedro R Cutillas, David Martín-Oliva.

  Poly(ADP-ribose) Polymerase 1 (PARP-1) is a nuclear enzyme that catalyse the transfer of ADP-ribose units from NAD+ to several target proteins involved in cellular stress responses. Using WRL68 (HeLa derivate) cells, we previously showed that PARP-1 activation induced by oxidative stress after H2O2 treatment lead to depletion of cellular NAD+ and ATP, which promoted cell death. In this work, LC-MS/MS based phosphoproteomics in WRL68 cells showed that the oxidative damage induced by H2O2 increased the phosphorylation of YAP1, a transcriptional coactivator involved in cell survival, and modified the phosphorylation of other proteins involved in transcription. Genetic or pharmacological inhibition of PARP-1 in H2O2-treated cells reduced YAP1 phosphorylation and degradation and increased cell viability. YAP1 silencing abrogated the protective effect of PARP-1 inhibition, indicating that YAP1 is important for the survival of WRL68 cells exposed to oxidative damage. Supplementation of NAD+ also reduced YAP1 phosphorylation, suggesting that the loss of cellular NAD+ caused by PARP-1 activation after oxidative treatment is responsible for the phosphorylation of YAP1. Finally, PARP-1 silencing after oxidative treatment diminished the activation of the metabolic sensor AMPK. Since, NAD+ supplementation reduced the phosphorylation of some AMPK substrates, we hypothesized that the loss of cellular NAD+ after PARP-1 activation may induce an energy stress that activates AMPK. In summary, we showed a new crucial role of PARP-1 in the response to oxidative stress in which PARP-1 activation reduced cell viability by promoting the phosphorylation and degradation of YAP1 through a mechanism that involves the depletion of NAD+.

Keywords:  LC-MS/MS; PARP-1; YAP1; cell survival; energy stress; phosphorylation

DOI:  https://doi.org/10.1042/BCJ20200525
Sci Immunol. 2020 Nov 06. pii: eabc4557. [Epub ahead of print]5(53):

Tissue-resident CD8+ T cells drive age-associated chronic lung sequelae after viral pneumonia.

Nick P Goplen, Yue Wu, Young Min Son, Chaofan Li, Zheng Wang, In Su Cheon, Li Jiang, Bibo Zhu, Katayoun Ayasoufi, Eduardo N Chini, Aaron J Johnson, Robert Vassallo, Andrew H Limper, Nu Zhang, Jie Sun.

Lower respiratory viral infections, such as influenza virus and severe acute respiratory syndrome coronavirus 2 infections, often cause severe viral pneumonia in aged individuals. Here, we report that influenza viral pneumonia leads to chronic nonresolving lung pathology and exacerbated accumulation of CD8+ tissue-resident memory T cells (TRM) in the respiratory tract of aged hosts. TRM cell accumulation relies on elevated TGF-β present in aged tissues. Further, we show that TRM cells isolated from aged lungs lack a subpopulation characterized by expression of molecules involved in TCR signaling and effector function. Consequently, TRM cells from aged lungs were insufficient to provide heterologous protective immunity. The depletion of CD8+ TRM cells dampens persistent chronic lung inflammation and ameliorates tissue fibrosis in aged, but not young, animals. Collectively, our data demonstrate that age-associated TRM cell malfunction supports chronic lung inflammatory and fibrotic sequelae after viral pneumonia.

DOI: https://doi.org/10.1126/sciimmunol.abc4557
Curr Dev Nutr. 2020 Oct;4(10): nzaa153

The Roles of Mitochondrial Folate Metabolism in Supporting Mitochondrial DNA Synthesis, Oxidative Phosphorylation, and Cellular Function.

Yuwen Xiu, Martha S Field.

  Folate-mediated one-carbon metabolism (FOCM) is compartmentalized within human cells to the cytosol, nucleus, and mitochondria. The recent identifications of mitochondria-specific, folate-dependent thymidylate [deoxythymidine monophosphate (dTMP)] synthesis together with discoveries indicating the critical role of mitochondrial FOCM in cancer progression have renewed interest in understanding this metabolic pathway. The goal of this narrative review is to summarize recent advances in the field of one-carbon metabolism, with an emphasis on the biological importance of mitochondrial FOCM in maintaining mitochondrial DNA integrity and mitochondrial function, as well as the reprogramming of mitochondrial FOCM in cancer. Elucidation of the roles and regulation of mitochondrial FOCM will contribute to a better understanding of the mechanisms underlying folate-associated pathologies.

Keywords:  cancer metabolism; folate; mitochondrial DNA; mitochondrial metabolism; thymidylate

DOI:  https://doi.org/10.1093/cdn/nzaa153