bims-imseme 2022-10-30 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2022–10–30
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Immunosenescence of T cells: a key player in rheumatoid arthritis.
The immune synapses reveal aberrant functions of CD8 T cells during chronic HIV infection.
Autophagic flux restoration enhances the antitumor efficacy of tumor infiltrating lymphocytes.
From thymus to tissues and tumors: a review of T cell biology.
Targeting T cell (oxidative) metabolism to improve immunity to viral infection in the context of obesity.
CD8+ T cells induce interferon-responsive oligodendrocytes and microglia in white matter aging.
G9a Modulates Lipid Metabolism in CD4 T cells to Regulate Intestinal Inflammation.
Self-reactivity of CD8 T-cell clones determines their differentiation status rather than their responsiveness in infections.
Mitochondrial dysfunction reactivates α-fetoprotein expression that drives copper-dependent immunosuppression in mitochondrial disease models.
Targeted Anti-Mitochondrial Therapy: The Future of Oncology.

Inflamm Res. 2022 Oct 25.

Immunosenescence of T cells: a key player in rheumatoid arthritis.

Yi Gao, Weiwei Cai, Ying Zhou, Yuhui Li, Jingwen Cheng, Fang Wei.

   INTRODUCTION: The incidence of rheumatoid arthritis (RA) and its complications are expected to increase with age. Remarkably, RA patients were identified features of accelerated aging, particularly in immunosenescence. As is known, T cells in RA patients readily differentiate into pro-inflammatory phenotypes that maintain chronic and persistent inflammatory changes in joints and many other organ systems. Recent evidence suggests that T cells are most sensitive to aging, and aged CD4+ T cells contribute to inflammaging, which plays a crucial role in accelerating the disease process. In recent years, the molecular mechanisms of T cell immunosenescence were beginning to be understood. Immune aging in RA T cells is associated with thymus insufficiency, metabolic abnormalities, shortened telomere length, and chronic energy stress. Therefore, we summarized the role and mechanism of T cell immunosenescence in RA.
METHODS: A computer-based online search was performed using the PubMed database for published articles concerning T cells aging and rheumatoid arthritis.
RESULTS: In this review, we assess the roles of CD4+ T cells in the center of inflammaging especially in RA and emphasize arthritogenic effector functions of senescent T cell; also we discuss the possible molecular mechanisms of senescent T cells and therapeutic targets to intervene T cells immunosenescence for improvement of RA.

Keywords:  Autoimmunity; Chronic inflammation; Immunosenescence; Rheumatoid arthritis; T cell aging

DOI:  https://doi.org/10.1007/s00011-022-01649-0
Nat Commun. 2022 Oct 28. 13(1): 6436

The immune synapses reveal aberrant functions of CD8 T cells during chronic HIV infection.

Nadia Anikeeva, Maria Steblyanko, Leticia Kuri-Cervantes, Marcus Buggert, Michael R Betts, Yuri Sykulev.

Chronic HIV infection causes persistent low-grade inflammation that induces premature aging of the immune system including senescence of memory and effector CD8 T cells. To uncover the reasons of gradually diminished potency of CD8 T cells from people living with HIV, here we expose the T cells to planar lipid bilayers containing ligands for T-cell receptor and a T-cell integrins and analyze the cellular morphology, dynamics of synaptic interface formation and patterns of the cellular degranulation. We find a large fraction of phenotypically naive T cells from chronically infected people are capable to form mature synapse with focused degranulation, a signature of a differentiated T cells. Further, differentiation of aberrant naive T cells may lead to the development of anomalous effector T cells undermining their capacity to control HIV and other pathogens that could be contained otherwise.

DOI: https://doi.org/10.1038/s41467-022-34157-0
J Immunother Cancer. 2022 Oct;pii: e004868. [Epub ahead of print]10(10):

Autophagic flux restoration enhances the antitumor efficacy of tumor infiltrating lymphocytes.

Chaoting Zhang, Yizhe Sun, Shance Li, Luyan Shen, Xia Teng, Yefei Xiao, Nan Wu, Zheming Lu.

   BACKGROUND: Although adoptive cell therapy with tumor infiltrating lymphocytes (TILs) has mediated effective antitumor responses in several cancers, dysfunction and exhaustion of TILs significantly impair the therapeutic effect of TILs. Thus, it is essential to elucidate the exhausted characteristics of TILs and improve the antitumor effect of TILs by reversing their exhaustion. Here, we focused on the influence of autophagy on TILs in terms of T-cell activation, proliferation, and differentiation in vitro and in vivo.
METHODS: We first evaluated autophagy level of TILs and influence of spermidine treatment on autophagy levels of TILs. Furthermore, we assessed the proliferative potential, phenotypical characteristics, T cell receptor (TCR) repertoire and antitumor activity of TILs with and without spermidine treatment.
RESULTS: We found that autophagic flux of TILs, especially exhausted TILs that express inhibitory immunoreceptors and have impaired proliferative capacity and decreased production of cytotoxic effector molecules, was significantly impaired. The restoration of autophagic flux via spermidine treatment resulted in increased diversity of the TCR repertoire, reduced expression of inhibitory immunoreceptors (PD1, TIM3, or LAG3), enhanced proliferation and effector functions, which subsequently demonstrated the superior in vitro and in vivo antitumor activity of TILs. Our findings unveil that spermidine, as an autophagy inducer, reverses dysfunction and exhaustion of TILs and subsequently improves the antitumor activity of TILs.
CONCLUSIONS: These data suggest that spermidine treatment presents an opportunity to improve adoptive TIL therapy for the treatment of solid tumors.

Keywords:  Immunotherapy, Adoptive; T-Lymphocytes

DOI:  https://doi.org/10.1136/jitc-2022-004868
J Allergy Clin Immunol. 2022 Oct 19. pii: S0091-6749(22)01378-1. [Epub ahead of print]

From thymus to tissues and tumors: a review of T cell biology.

Laura Chopp, Christopher Redmond, John J O'Shea, Daniella M Schwartz.

T cells are critical orchestrators of the adaptive immune response that optimally eliminates a specific pathogen. Aberrant T cell development and function are implicated in a broad range of human disease including immunodeficiencies, autoimmune diseases, and allergic diseases. Accordingly, therapies targeting T cells and their effector cytokines have drastically improved the care of patients with immune dysregulatory diseases. Newer discoveries concerning T cell mediated antitumor immunity and T cell exhaustion have further prompted development of highly effective and novel treatment modalities for malignancies, including checkpoint inhibitors and antigen-reactive T cells. Recent discoveries are also uncovering the depth and variability of T cell phenotypes: while T cells have long been described using a subset-based classification system, next-generation sequencing technologies suggest an astounding degree of complexity and heterogeneity at the single cell level.

DOI: https://doi.org/10.1016/j.jaci.2022.10.011
Front Immunol. 2022 ;13 1025495

Targeting T cell (oxidative) metabolism to improve immunity to viral infection in the context of obesity.

Elizabeth Greene, Nancie J MacIver.

  Disorders of systemic metabolism can influence immunity. Individuals with obesity are known to have increased inflammation, increased risk to select autoimmune diseases, impaired response to several infections, and impaired vaccine response. For example, over the last decade, it has become clear that individuals with obesity have increased risk of morbidity and mortality from influenza infection. Unsurprisingly, this finding is also observed in the current COVID-19 pandemic: individuals with obesity, particularly severe obesity, have increased risk of poor outcomes from SARS-CoV-2 infection, including increased rates of hospitalization, ICU admission, mechanical ventilation, and death. Several studies have now demonstrated a critical role for T cells in the context of obesity-associated immune dysfunction in response to viral infection, and one mechanism for this may be altered T cell metabolism. Indeed, recent studies have shown that activated T cells from obese mice have an altered metabolic profile characterized by increased glucose oxidation, both in vitro and in vivo following viral infection. For that reason, treatments that target abnormal immune cell metabolism in obesity may improve outcomes to viral infection. To that end, several recent studies have shown that use of the metabolic drug, metformin, can reverse abnormal T cell metabolism and restore T cell immunity, as well as survival, in response to viral infection. These findings will be discussed in detail here.

Keywords:  T cells; coronavirus disease 2019 (COVID-19); influenza; metabolism; metformin; obesity

DOI:  https://doi.org/10.3389/fimmu.2022.1025495
Nat Neurosci. 2022 Oct 24.

CD8+ T cells induce interferon-responsive oligodendrocytes and microglia in white matter aging.

Tuğberk Kaya, Nicola Mattugini, Lu Liu, Hao Ji, Ludovico Cantuti-Castelvetri, Jianping Wu, Martina Schifferer, Janos Groh, Rudolf Martini, Simon Besson-Girard, Seiji Kaji, Arthur Liesz, Ozgun Gokce, Mikael Simons.

A hallmark of nervous system aging is a decline of white matter volume and function, but the underlying mechanisms leading to white matter pathology are unknown. In the present study, we found age-related alterations of oligodendrocyte cell state with a reduction in total oligodendrocyte density in aging murine white matter. Using single-cell RNA-sequencing, we identified interferon (IFN)-responsive oligodendrocytes, which localize in proximity to CD8+ T cells in aging white matter. Absence of functional lymphocytes decreased the number of IFN-responsive oligodendrocytes and rescued oligodendrocyte loss, whereas T-cell checkpoint inhibition worsened the aging response. In addition, we identified a subpopulation of lymphocyte-dependent, IFN-responsive microglia in the vicinity of the CD8+ T cells in aging white matter. In summary, we provide evidence that CD8+ T-cell-induced, IFN-responsive oligodendrocytes and microglia are important modifiers of white matter aging.

DOI: https://doi.org/10.1038/s41593-022-01183-6
Gastroenterology. 2022 Oct 19. pii: S0016-5085(22)01185-4. [Epub ahead of print]

G9a Modulates Lipid Metabolism in CD4 T cells to Regulate Intestinal Inflammation.

Guilherme Piovezani Ramos, Adebowale O Bamidele, Emily E Klatt, Mary R Sagstetter, Ahmed T Kurdi, Feda H Hamdan, Robyn Laura Kosinsky, Joseph M Gaballa, Asha Nair, Zhifu Sun, Surendra Dasari, Ian R Lanza, Cody N Rozeveld, Micah B Schott, Guillermo Urrutia, Maria S Westphal, Benjamin D Clarkson, Charles L Howe, Eric V Marietta, David H Luckey, Joseph A Murray, Michelle Gonzalez, Manuel B Braga Neto, Hunter R Gibbons, Thomas C Smyrk, Steven Johnsen, Gwen Lomberk, William A Faubion.

   BACKGROUND: /Aims: Although T cell intrinsic expression of G9a has been associated with murine intestinal inflammation, mechanistic insight into the role of this methyltransferase in human T cell differentiation is ill-defined and manipulation of G9a function for therapeutic use against inflammatory disorders is unexplored.
METHODS: Human naïve T cells were isolated from peripheral blood and differentiated in vitro in the presence of a G9a inhibitor (UNC0642) prior to being characterized via the transcriptome (RNA-seq), chromatin accessibility (ATAC-seq), protein expression (CyTOF, flow cytometry), metabolism (mitochondrial stress test, UPLC-MS/MS) and function (T cell suppression assay). In vivo role of G9a was assessed using three murine models.
RESULTS: We discovered that pharmacologic inhibition of G9a enzymatic function in human CD4 T cells led to spontaneous generation of FOXP3+ T cells (G9ai-Tregs) in vitro that faithfully reproduce human Tregs, functionally and phenotypically. Mechanistically, G9a inhibition altered the transcriptional regulation of genes involved in lipid biosynthesis in T cells resulting in increased intracellular cholesterol. Metabolomic profiling of G9ai-Tregs confirmed elevated lipid pathways that support Treg development through oxidative phosphorylation and enhanced lipid membrane composition. Pharmacologic G9a inhibition promoted Treg expansion in vivo upon antigen (gliadin) stimulation and ameliorated acute TNBS-induced colitis secondary to tissue specific Treg development. Lastly, Tregs lacking G9a expression (G9aKO Tregs) remain functional chronically and can rescue T cell transfer induced colitis.
CONCLUSION: G9a inhibition promotes cholesterol metabolism in T cells favoring a metabolic profile that facilitates Treg development in vitro and in vivo. Our data support the potential use of G9a inhibitors in the treatment of immune-mediated conditions including inflammatory bowel disease.

Keywords:  Cholesterol; Inflammatory Bowel Disease; Lipid Metabolism; Regulatory T cells

DOI:  https://doi.org/10.1053/j.gastro.2022.10.011
Front Immunol. 2022 ;13 1009198

Self-reactivity of CD8 T-cell clones determines their differentiation status rather than their responsiveness in infections.

Darina Paprckova, Veronika Niederlova, Alena Moudra, Ales Drobek, Michaela Pribikova, Sarka Janusova, Kilian Schober, Ales Neuwirth, Juraj Michalik, Martina Huranova, Veronika Horkova, Michaela Cesnekova, Michaela Simova, Jan Prochazka, Jana Balounova, Dirk H Busch, Radislav Sedlacek, Martin Schwarzer, Ondrej Stepanek.

  Mature T cells are selected for recognizing self-antigens with low to intermediate affinity in the thymus. Recently, the relative differences in self-reactivity among individual T-cell clones were appreciated as important factors regulating their fate and immune response, but the role of self-reactivity in T-cell biology is incompletely understood. We addressed the role of self-reactivity in T-cell diversity by generating an atlas of mouse peripheral CD8+ T cells, which revealed two unconventional populations of antigen-inexperienced T cells. In the next step, we examined the steady-state phenotype of monoclonal T cells with various levels of self-reactivity. Highly self-reactive clones preferentially differentiate into antigen-inexperienced memory-like cells, but do not form a population expressing type I interferon-induced genes, showing that these two subsets have unrelated origins. The functional comparison of naïve monoclonal CD8+ T cells specific to the identical model antigen did not show any correlation between the level of self-reactivity and the magnitude of the immune response.

Keywords:  T cell; T-cell diversity; antigen-inexperienced memory-like CD8 T cells; interferon response; self-reactivity

DOI:  https://doi.org/10.3389/fimmu.2022.1009198
J Clin Invest. 2022 Oct 27. pii: e154684. [Epub ahead of print]

Mitochondrial dysfunction reactivates α-fetoprotein expression that drives copper-dependent immunosuppression in mitochondrial disease models.

Kimberly A Jett, Zakery N Baker, Amzad Hossain, Aren Boulet, Paul A Cobine, Sagnika Ghosh, Philip Ng, Orhan Yilmaz, Kris Barreto, John DeCoteau, Karen Mochoruk, George N Ioannou, Christopher Savard, Sai Yuan, Osama Hmh Abdalla, Christopher Lowden, Byung-Eun Kim, Hai-Ying Mary Cheng, Brendan J Battersby, Vishal M Gohil, Scot C Leary.

  Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many metabolic disorders. Here, we identify a copper-linked signaling circuit activated by disruption of mitochondrial function in the murine liver or heart that results in atrophy of the spleen and thymus and causes a peripheral white blood cell deficiency. We demonstrate that the leukopenia is caused by α-fetoprotein, which requires copper and the cell surface receptor CCR5 to promote white blood cell death. We further show that α-fetoprotein expression is upregulated in several cell types upon inhibition of oxidative phosphorylation, including a muscle cell model of Barth syndrome. Collectively, our data argue that α-fetoprotein secreted by bioenergetically stressed tissue suppresses the immune system, an effect which may explain the recurrent infections that are observed in a subset of mitochondrial diseases or in other disorders with mitochondrial involvement.

Keywords:  Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/JCI154684
Genes (Basel). 2022 Sep 26. pii: 1728. [Epub ahead of print]13(10):

Targeted Anti-Mitochondrial Therapy: The Future of Oncology.

Farzad Taghizadeh-Hesary, Hassan Akbari, Moslem Bahadori, Babak Behnam.

  Like living organisms, cancer cells require energy to survive and interact with their environment. Mitochondria are the main organelles for energy production and cellular metabolism. Recently, investigators demonstrated that cancer cells can hijack mitochondria from immune cells. This behavior sheds light on a pivotal piece in the cancer puzzle, the dependence on the normal cells. This article illustrates the benefits of new functional mitochondria for cancer cells that urge them to hijack mitochondria. It describes how functional mitochondria help cancer cells' survival in the harsh tumor microenvironment, immune evasion, progression, and treatment resistance. Recent evidence has put forward the pivotal role of mitochondria in the metabolism of cancer stem cells (CSCs), the tumor components responsible for cancer recurrence and metastasis. This theory highlights the mitochondria in cancer biology and explains how targeting mitochondria may improve oncological outcomes.

Keywords:  ATP; T cell; cancer cell; cancer stem cell; cancer treatment; mitochondria

DOI:  https://doi.org/10.3390/genes13101728