bims-imseme 2023-01-22 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2023–01–22
sixteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Exhausted T cells in tumors gain suppressor activity and can restrain immunity.
Functional T cells are capable of supernumerary cell division and longevity.
The emerging role of the branched chain aminotransferases, BCATc and BCATm, for anti-tumor T-cell immunity.
IFNγ signaling in cytotoxic T cells restricts anti-tumor responses by inhibiting the maintenance and diversity of intra-tumoral stem-like T cells.
Epigenetics in T-cell driven inflammation and cancer.
Imaging polarized granule release at the cytotoxic T cell immunological synapse using TIRF microscopy: Control by polarity regulators.
Cancer cells resistant to immune checkpoint blockade acquire interferon-associated epigenetic memory to sustain T cell dysfunction.
Tackling Inflammation at its Source in Heart Failure: Are Mitochondria the Key?
Immunometabolism and microbial metabolites at the gut barrier: lessons for therapeutic intervention in Inflammatory Bowel Disease.
Shaping immunity for life: Layered development of CD8+ T cells.
Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating CD8+ T cells.
Nitro-oleic acid regulates T cell activation through post-translational modification of calcineurin.
Reprogramming dysfunctional CD8+ T cells to promote properties associated with natural HIV control.
Mitochondrial stress and mitokines in aging.
Soluble CD25 imposes a low-zone IL-2 signaling environment that favors competitive outgrowth of antigen-experienced CD25high regulatory and memory T cells.
Quantifying changes in the T cell receptor repertoire during thymic development.

Nat Immunol. 2023 Jan 17.

Exhausted T cells in tumors gain suppressor activity and can restrain immunity.

DOI: https://doi.org/10.1038/s41590-022-01409-6
Nature. 2023 Jan 18.

Functional T cells are capable of supernumerary cell division and longevity.

Andrew G Soerens, Marco Künzli, Clare F Quarnstrom, Milcah C Scott, Lee Swanson, J J Locquiao, Hazem E Ghoneim, Dietmar Zehn, Benjamin Youngblood, Vaiva Vezys, David Masopust.

Differentiated somatic mammalian cells putatively exhibit species-specific division limits that impede cancer but may constrain lifespans1-3. To provide immunity, transiently stimulated CD8+ T cells undergo unusually rapid bursts of numerous cell divisions, and then form quiescent long-lived memory cells that remain poised to reproliferate following subsequent immunological challenges. Here we addressed whether T cells are intrinsically constrained by chronological or cell-division limits. We activated mouse T cells in vivo using acute heterologous prime-boost-boost vaccinations4, transferred expanded cells to new mice, and then repeated this process iteratively. Over 10 years (greatly exceeding the mouse lifespan)5 and 51 successive immunizations, T cells remained competent to respond to vaccination. Cells required sufficient rest between stimulation events. Despite demonstrating the potential to expand the starting population at least 1040-fold, cells did not show loss of proliferation control and results were not due to contamination with young cells. Persistent stimulation by chronic infections or cancer can cause T cell proliferative senescence, functional exhaustion and death6. We found that although iterative acute stimulations also induced sustained expression and epigenetic remodelling of common exhaustion markers (including PD1, which is also known as PDCD1, and TOX) in the cells, they could still proliferate, execute antimicrobial functions and form quiescent memory cells. These observations provide a model to better understand memory cell differentiation, exhaustion, cancer and ageing, and show that functionally competent T cells can retain the potential for extraordinary population expansion and longevity well beyond their organismal lifespan.

DOI: https://doi.org/10.1038/s41586-022-05626-9
Immunometabolism (Cobham). 2023 Jan;5(1): e00014

The emerging role of the branched chain aminotransferases, BCATc and BCATm, for anti-tumor T-cell immunity.

Tanner J Wetzel, Sheila C Erfan, Elitsa A Ananieva.

  Challenges regarding successful immunotherapy are associated with the heterogeneity of tumors and the complex interactions within the surrounding tumor microenvironment (TME), particularly those between immune and tumor cells. Of interest, T cells receive a myriad of environmental signals to elicit differentiation to effector subtypes, which is accompanied by metabolic reprogramming needed to satisfy the high energy and biosynthetic demands of their activated state. However, T cells are subjected to immunosuppressive signals and areas of oxygen and nutrient depletion in the TME, which causes T-cell exhaustion and helps tumor cells escape immune detection. The cytosolic and mitochondrial branched chain amino transferases, BCATc and BCATm, respectively, are responsible for the first step of the branched chain amino acid (BCAA) degradation, of which, metabolites are shunted into various metabolic processes. In recent years, BCAT isoenzymes have been investigated for their role in a variety of cancers found throughout the body; however, a gap of knowledge exists regarding the role BCAT isoenzymes play within immune cells of the TME. The aim of this review is to summarize recent findings about BCAAs and their catabolism at the BCAT step during T-cell metabolic reprogramming and to discuss the BCAT putative role in the anti-tumor immunity of T cells. Not only does this review acknowledges gaps pertaining to BCAA metabolism in the TME but it also identifies the practical application of BCAA metabolism in T cells in response to cancer and spotlights a potential target for pharmacological intervention.

Keywords:  BCAA; BCATc; BCATm; TME; immunotherapy; leucine

DOI:  https://doi.org/10.1097/IN9.0000000000000014
Nat Commun. 2023 Jan 19. 14(1): 321

IFNγ signaling in cytotoxic T cells restricts anti-tumor responses by inhibiting the maintenance and diversity of intra-tumoral stem-like T cells.

Julie M Mazet, Jagdish N Mahale, Orion Tong, Robert A Watson, Ana Victoria Lechuga-Vieco, Gabriela Pirgova, Vivian W C Lau, Moustafa Attar, Lada A Koneva, Stephen N Sansom, Benjamin P Fairfax, Audrey Gérard.

IFNγ is an immune mediator with concomitant pro- and anti-tumor functions. Here, we provide evidence that IFNγ directly acts on intra-tumoral CD8 T cells to restrict anti-tumor responses. We report that expression of the IFNγ receptor β chain (IFNγR2) in CD8 T cells negatively correlates with clinical responsiveness to checkpoint blockade in metastatic melanoma patients, suggesting that the loss of sensitivity to IFNγ contributes to successful antitumor immunity. Indeed, specific deletion of IFNγR in CD8 T cells promotes tumor control in a mouse model of melanoma. Chronic IFNγ inhibits the maintenance, clonal diversity and proliferation of stem-like T cells. This leads to decreased generation of T cells with intermediate expression of exhaustion markers, previously associated with beneficial anti-tumor responses. This study provides evidence of a negative feedback loop whereby IFNγ depletes stem-like T cells to restrict anti-tumor immunity. Targeting this pathway might represent an alternative strategy to enhance T cell-based therapies.

DOI: https://doi.org/10.1038/s41467-023-35948-9
Semin Cell Dev Biol. 2023 Jan 12. pii: S1084-9521(23)00008-3. [Epub ahead of print]

Epigenetics in T-cell driven inflammation and cancer.

Lea Falkowski, Joerg Buddenkotte, Angeliki Datsi.

  For decades, scientists have been investigating how processes such as gene expression, stem cell plasticity, and cell differentiation can be modulated. The discovery of epigenetics helped unravel these processes and enabled the identification of major underlying mechanisms that, for example, are central for T cell maturation. T cells go through various stages in their development evolving from progenitor cells into double positive CD4/CD8 T cells that finally leave the thymus as naïve T cells. One major mechanism driving T cell maturation is the modulation of gene activity by temporally sequenced transcription of spatially exposed gene loci. DNA methylation, demethylation, and acetylation are key processes that enable a sequenced gene expression required for T cell differentiation. In vivo, differentiated T cells are subjected to enormous pressures originating from the microenvironment. Signals from this environment, particularly from an inflammatory or a tumor microenvironment, can push T cells to differentiate into specific effector and memory T cells, and even prompt T cells to adopt a state of dysfunctional exhaustion, en route of an epigenetically controlled mechanism. Fundamentals of these processes will be discussed in this review highlighting potential therapeutic interventions, in particular those beneficial to revive exhausted T cells.

Keywords:  Anti-tumor vaccine; Epigenetics; ICI-treatment; T cell differentiation; T cell exhaustion

DOI:  https://doi.org/10.1016/j.semcdb.2023.01.008
Methods Cell Biol. 2023 ;pii: S0091-679X(22)00107-8. [Epub ahead of print]173 1-13

Imaging polarized granule release at the cytotoxic T cell immunological synapse using TIRF microscopy: Control by polarity regulators.

Marie Juzans, Céline Cuche, Vincenzo Di Bartolo, Andrés Alcover.

  Immunological synapse formation results from a profound T cell polarization process that involves the coordinated action of the actin and microtubule cytoskeleton, and the intracellular traffic of several vesicular organelles. T cell polarization is key for both T cell activation leading to T cell proliferation and differentiation, and for T cell effector functions such as polarized secretion of cytokines by helper T cells, or polarized delivery of lytic granules by cytotoxic T cells. Efficient targeting of lytic granules by cytotoxic T cells is a crucial event for the control and elimination of infected or tumor cells. Understanding how lytic granule delivery is regulated and quantifying its efficiency under physiological and pathological conditions may help to improve immune responses against infection and cancer.

Keywords:  Cytotoxic T cells; Immunological synapse; Lytic granules; Polarity regulators; Polarized released; TIRF microscopy

DOI:  https://doi.org/10.1016/bs.mcb.2022.07.016
Nat Cancer. 2023 Jan 16.

Cancer cells resistant to immune checkpoint blockade acquire interferon-associated epigenetic memory to sustain T cell dysfunction.

Jingya Qiu, Bihui Xu, Darwin Ye, Diqiu Ren, Shangshang Wang, Joseph L Benci, Yuanming Xu, Hemant Ishwaran, Jean-Christophe Beltra, E John Wherry, Junwei Shi, Andy J Minn.

Prolonged interferon (IFN) signaling in cancer cells can promote resistance to immune checkpoint blockade (ICB). How cancer cells retain effects of prolonged IFN stimulation to coordinate resistance is unclear. We show that, across human and/or mouse tumors, immune dysfunction is associated with cancer cells acquiring epigenetic features of inflammatory memory. Here, inflammatory memory domains, many of which are initiated by chronic IFN-γ, are maintained by signal transducer and activator of transcription (STAT)1 and IFN regulatory factor (IRF)3 and link histone 3 lysine 4 monomethylation (H3K4me1)-marked chromatin accessibility to increased expression of a subset of IFN-stimulated genes (ISGs). These ISGs include the RNA sensor OAS1 that amplifies type I IFN (IFN-I) and immune inhibitory genes. Abrogating cancer cell IFN-I signaling restores anti-programmed cell death protein 1 (PD1) response by increasing IFN-γ in immune cells, promoting dendritic cell and CD8+ T cell interactions, and expanding T cells toward effector-like states rather than exhausted states. Thus, cancer cells acquire inflammatory memory to augment a subset of ISGs that promote and predict IFN-driven immune dysfunction.

DOI: https://doi.org/10.1038/s43018-022-00490-y
JACC Basic Transl Sci. 2022 Dec;7(12): 1197-1199

Tackling Inflammation at its Source in Heart Failure: Are Mitochondria the Key?

Michael N Sack.



Keywords:  heart failure with reduced ejection fraction; mitochondrial function; nicotinamide adenine dinucleotide; nicotinamide riboside; sterile inflammation

DOI:  https://doi.org/10.1016/j.jacbts.2022.07.008
Mucosal Immunol. 2023 Jan 12. pii: S1933-0219(22)01180-1. [Epub ahead of print]

Immunometabolism and microbial metabolites at the gut barrier: lessons for therapeutic intervention in Inflammatory Bowel Disease.

Margret Michaels, Karen L Madsen.

  The concept of immunometabolism has emerged recently whereby repolarizing of inflammatory immune cells towards anti-inflammatory profiles by manipulating cellular metabolism represents a new potential therapeutic approach in controlling inflammation.Metabolic pathways in immune cells are tightly regulated to maintain immune homeostasis and appropriate functional specificity. As effector and regulatory immune cell populations have different metabolic requirements, this allows for cellular selectivity when regulating immune responses based on metabolic pathways. Gut microbes have a major role in modulating immune cell metabolic profiles and functional responses through extensive interactions involving metabolic products and crosstalk between gut microbes, intestinal epithelial cells, and mucosal immune cells. Developing strategies to target metabolic pathways in mucosal immune cells through modulation of gut microbial metabolism has the potential for new therapeutic approaches for human autoimmune and inflammatory diseases, such as inflammatory bowel disease. This review will give an overview of the relationship between metabolic reprogramming and immune responses, how microbial metabolites influence these interactions, and how these pathways could be harnessed in the treatment of inflammatory bowel disease.

Keywords:  immunometabolism; inflammatory bowel disease; microbiome

DOI:  https://doi.org/10.1016/j.mucimm.2022.11.001
Immunol Rev. 2023 Jan 18.

Shaping immunity for life: Layered development of CD8+ T cells.

Cybelle Tabilas, Norah L Smith, Brian D Rudd.

  Historically, the immune system was believed to develop along a linear axis of maturity from fetal life to adulthood. Now, it is clear that distinct layers of immune cells are generated from unique waves of hematopoietic progenitors during different windows of development. This model, known as the layered immune model, has provided a useful framework for understanding why distinct lineages of B cells and γδ T cells arise in succession and display unique functions in adulthood. However, the layered immune model has not been applied to CD8+ T cells, which are still often viewed as a uniform population of cells belonging to the same lineage, with functional differences between cells arising from environmental factors encountered during infection. Recent studies have challenged this idea, demonstrating that not all CD8+ T cells are created equally and that the functions of individual CD8+ T cells in adults are linked to when they were created in the host. In this review, we discuss the accumulating evidence suggesting there are distinct ontogenetic subpopulations of CD8+ T cells and propose that the layered immune model be extended to the CD8+ T cell compartment.

Keywords:  CD8+ T cells; Immune development; hematopoietic progenitor cells

DOI:  https://doi.org/10.1111/imr.13185
Mol Cell. 2023 Jan 11. pii: S1097-2765(22)01212-6. [Epub ahead of print]

Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating CD8+ T cells.

Dania Riegel, Elena Romero-Fernández, Malte Simon, Akinbami Raphael Adenugba, Katrin Singer, Roman Mayr, Florian Weber, Mark Kleemann, Charles D Imbusch, Marina Kreutz, Benedikt Brors, Ines Ugele, Jens M Werner, Peter J Siska, Christian Schmidl.

  Despite extensive studies on the chromatin landscape of exhausted T cells, the transcriptional wiring underlying the heterogeneous functional and dysfunctional states of human tumor-infiltrating lymphocytes (TILs) is incompletely understood. Here, we identify gene-regulatory landscapes in a wide breadth of functional and dysfunctional CD8+ TIL states covering four cancer entities using single-cell chromatin profiling. We map enhancer-promoter interactions in human TILs by integrating single-cell chromatin accessibility with single-cell RNA-seq data from tumor-entity-matching samples and prioritize cell-state-specific genes by super-enhancer analysis. Besides revealing entity-specific chromatin remodeling in exhausted TILs, our analyses identify a common chromatin trajectory to TIL dysfunction and determine key enhancers, transcriptional regulators, and deregulated genes involved in this process. Finally, we validate enhancer regulation at immunotherapeutically relevant loci by targeting non-coding regulatory elements with potent CRISPR activators and repressors. In summary, our study provides a framework for understanding and manipulating cell-state-specific gene-regulatory cues from human tumor-infiltrating lymphocytes.

Keywords:  CRISPR activation; CRISPR interference; T cell exhaustion; cancer immunology; chromatin accessibility; enhancer; gene regulation; single-cell ATAC-seq; tumor-infiltrating T cells

DOI:  https://doi.org/10.1016/j.molcel.2022.12.029
Proc Natl Acad Sci U S A. 2023 Jan 24. 120(4): e2208924120

Nitro-oleic acid regulates T cell activation through post-translational modification of calcineurin.

Ángel Bago, M Laura Cayuela, Alba Gil, Enrique Calvo, Jesús Vázquez, Antonio Queiro, Francisco J Schopfer, Rafael Radi, Juan M Serrador, Miguel A Íñiguez.

  Nitro-fatty acids (NO2-FAs) are unsaturated fatty acid nitration products that exhibit anti-inflammatory actions in experimental mouse models of autoimmune and allergic diseases. These electrophilic molecules interfere with intracellular signaling pathways by reversible post-translational modification of nucleophilic amino-acid residues. Several regulatory proteins have been identified as targets of NO2-FAs, modifying their activity and promoting gene expression changes that result in anti-inflammatory effects. Herein, we report the effects of nitro-oleic acid (NO2-OA) on pro-inflammatory T cell functions, showing that 9- and 10-NOA, but not their oleic acid precursor, decrease T cell proliferation, expression of activation markers CD25 and CD71 on the plasma membrane, and IL-2, IL-4, and IFN-γ cytokine gene expressions. Moreover, we have found that NO2-OA inhibits the transcriptional activity of nuclear factor of activated T cells (NFAT) and that this inhibition takes place through the regulation of the phosphatase activity of calcineurin (CaN), hindering NFAT dephosphorylation, and nuclear translocation in activated T cells. Finally, using mass spectrometry-based approaches, we have found that NO2-OA nitroalkylates CaNA on four Cys (Cys129, 228, 266, and 372), of which only nitroalkylation on Cys372 was of importance for the regulation of CaN phosphatase activity in cells, disturbing functional CaNA/CaNB heterodimer formation. These results provide evidence for an additional mechanism by which NO2-FAs exert their anti-inflammatory actions, pointing to their potential as therapeutic bioactive lipids for the modulation of harmful T cell-mediated immune responses.

Keywords:  NFAT; T cells; calcineurin; inflammation; nitro-fatty acids

DOI:  https://doi.org/10.1073/pnas.2208924120
J Clin Invest. 2023 Jan 17. pii: e167843. [Epub ahead of print]133(2):

Reprogramming dysfunctional CD8+ T cells to promote properties associated with natural HIV control.

Federico Perdomo-Celis, Caroline Passaes, Valérie Monceaux, Stevenn Volant, Faroudy Boufassa, Pierre de Truchis, Morgane Marcou, Katia Bourdic, Laurence Weiss, Corinne Jung, Christine Bourgeois, Cécile Goujard, Laurence Meyer, Michaela Müller-Trutwin, Olivier Lambotte, Asier Sáez-Cirión.

DOI: https://doi.org/10.1172/JCI167843
Aging Cell. 2023 Jan 15. e13770

Mitochondrial stress and mitokines in aging.

Johannes Burtscher, Afsaneh Soltany, Nishant P Visavadiya, Martin Burtscher, Grégoire P Millet, Kayvan Khoramipour, Andy V Khamoui.

  Mitokines are signaling molecules that enable communication of local mitochondrial stress to other mitochondria in distant cells and tissues. Among those molecules are FGF21, GDF15 (both expressed in the nucleus) and several mitochondrial-derived peptides, including humanin. Their responsiveness to mitochondrial stress induces mitokine-signaling in response for example to exercise, following mitochondrial challenges in skeletal muscle. Such signaling is emerging as an important mediator of exercise-derived and dietary strategy-related molecular and systemic health benefits, including healthy aging. A compensatory increase in mitokine synthesis and secretion could preserve mitochondrial function and overall cellular vitality. Conversely, resistance against mitokine actions may also develop. Alterations of mitokine-levels, and therefore of mitokine-related inter-tissue cross talk, are associated with general aging processes and could influence the development of age-related chronic metabolic, cardiovascular and neurological diseases; whether these changes contribute to aging or represent "rescue factors" remains to be conclusively shown. The aim of the present review is to summarize the expanding knowledge on mitokines, the potential to modulate them by lifestyle and their involvement in aging and age-related diseases. We highlight the importance of well-balanced mitokine-levels, the preventive and therapeutic properties of maintaining mitokine homeostasis and sensitivity of mitokine signaling but also the risks arising from the dysregulation of mitokines. While reduced mitokine levels may impair inter-organ crosstalk, also excessive mitokine concentrations can have deleterious consequences and are associated with conditions such as cancer and heart failure. Preservation of healthy mitokine signaling levels can be achieved by regular exercise and is associated with an increased lifespan.

Keywords:  FGF21; GDF15; humanin; mitochondria-derived peptides; mitochondrial stress response; mitohormesis; mitokines

DOI:  https://doi.org/10.1111/acel.13770
Cell Immunol. 2023 Jan 05. pii: S0008-8749(23)00003-5. [Epub ahead of print]384 104664

Soluble CD25 imposes a low-zone IL-2 signaling environment that favors competitive outgrowth of antigen-experienced CD25high regulatory and memory T cells.

Rebecca A Nickle, Kayla B DeOca, Brandon L Garcia, Mark D Mannie.

  This study focused on soluble (s)CD25-mediated regulation of IL-2 signaling in murine and human CD4+ T cells. Recombinant sCD25 reversibly sequestered IL-2 to limit acute maximal proliferative responses while preserving IL-2 bioavailability to subsequently maintain low-zone IL-2 signaling during prolonged culture. By inhibiting IL-2 signaling during acute activation, sCD25 suppressed T-cell growth and inhibited IL-2-evoked transmembrane CD25 expression, thereby resulting in lower prevalence of CD25high T cells. By inhibiting IL-2 signaling during quiescent IL-2-mediated growth, sCD25 competed with transmembrane CD25, IL2Rβγ, and IL2Rαβγ receptors for limited pools of IL-2 such that sCD25 exhibited strong or weak inhibitory efficacy in IL-2-stimulated cultures of CD25low or CD25high T cells, respectively. Preferential blocking of IL-2 signaling in CD25low but not CD25high T cells caused competitive enrichment of CD25high memory/effector and regulatory FOXP3+ subsets. In conclusion, sCD25 modulates IL-2 bioavailability to limit CD25 expression during acute activation while enhancing CD25highT-cell dominance during low-zone homeostatic IL-2-mediated expansion, thereby 'flattening' the inflammatory curve over time.

Keywords:  CD25(high) T cells; Cell culture; Conventional T cells; FOXP3(+) regulatory T cells; Human and Mouse T cells; IL-2; IL2Rα; Soluble CD25 or sCD25; T cell activation; Transmembrane CD25

DOI:  https://doi.org/10.1016/j.cellimm.2023.104664
Elife. 2023 Jan 20. pii: e81622. [Epub ahead of print]12

Quantifying changes in the T cell receptor repertoire during thymic development.

Francesco Camaglia, Arie Ryvkin, Erez Greenstein, Shlomit Reich-Zeliger, Benny Chain, Thierry Mora, Aleksandra M Walczak, Nir Friedman.

  One of the feats of adaptive immunity is its ability to recognize foreign pathogens while sparing the self. During maturation in the thymus, T cells are selected through the binding properties of their antigen-specific T-cell receptor (TCR), through the elimination of both weakly (positive selection) and strongly (negative selection) self-reactive receptors. However, the impact of thymic selection on the TCR repertoire is poorly understood. Here, we use transgenic Nur77-mice expressing a T-cell activation reporter to study the repertoires of thymic T cells at various stages of their development, including cells that do not pass selection. We combine high-throughput repertoire sequencing with statistical inference techniques to characterize the selection of the TCR in these distinct subsets. We find small but significant differences in the TCR repertoire parameters between the maturation stages, which recapitulate known differentiation pathways leading to the CD4+ and CD8+ subtypes. These differences can be simulated by simple models of selection acting linearly on the sequence features. We find no evidence of specific sequences or sequence motifs or features that are suppressed by negative selection. These results favour a collective or statistical model for T-cell self non-self discrimination, where negative selection biases the repertoire away from self recognition, rather than ensuring lack of self-reactivity at the single-cell level.

Keywords:  immunology; inflammation; mouse; physics of living systems

DOI:  https://doi.org/10.7554/eLife.81622