bims-imseme 2022-03-27 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2022–03–27
eleven papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

CD5 Deficiency Alters Helper T Cell Metabolic Function and Shifts the Systemic Metabolome.
The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming.
1,25-dihydroxyvitamin D3 suppresses CD4+ T cell effector functionality by inhibition of glycolysis.
Androgen receptor activity in T cells limits checkpoint blockade efficacy.
Telomerase deficiency reflects age-associated changes in CD4+ T cells.
CD8+ T cells PUF(A)ing the flames of cancer ferroptotic cell death.
1α,25(OH)2D3 reverses exhaustion and enhances antitumor immunity of human cytotoxic T cells.
CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity.
Telomere length and vitamin B12.
CD8+ T Cell Senescence: Lights and Shadows in Viral Infections, Autoimmune Disorders and Cancer.
Gut-derived bacterial toxins impair memory CD4 T-cell mitochondrialfunction in HIV-1infection.

Biomedicines. 2022 Mar 18. pii: 704. [Epub ahead of print]10(3):

CD5 Deficiency Alters Helper T Cell Metabolic Function and Shifts the Systemic Metabolome.

Kiara V Whitley, Claudia M Tellez Freitas, Carlos Moreno, Christopher Haynie, Joshua Bennett, John C Hancock, Tyler D Cox, Brett E Pickett, K Scott Weber.

  Metabolic function plays a key role in immune cell activation, destruction of foreign pathogens, and memory cell generation. As T cells are activated, their metabolic profile is significantly changed due to signaling cascades mediated by the T cell receptor (TCR) and co-receptors found on their surface. CD5 is a T cell co-receptor that regulates thymocyte selection and peripheral T cell activation. The removal of CD5 enhances T cell activation and proliferation, but how this is accomplished is not well understood. We examined how CD5 specifically affects CD4+ T cell metabolic function and systemic metabolome by analyzing serum and T cell metabolites from CD5WT and CD5KO mice. We found that CD5 removal depletes certain serum metabolites, and CD5KO T cells have higher levels of several metabolites. Transcriptomic analysis identified several upregulated metabolic genes in CD5KO T cells. Bioinformatic analysis identified glycolysis and the TCA cycle as metabolic pathways promoted by CD5 removal. Functional metabolic analysis demonstrated that CD5KO T cells have higher oxygen consumption rates (OCR) and higher extracellular acidification rates (ECAR). Together, these findings suggest that the loss of CD5 is linked to CD4+ T cell metabolism changes in metabolic gene expression and metabolite concentration.

Keywords:  CD5; RNA-Seq; T cell co-receptor; T cell metabolism; bioinformatics; helper T cell; metabolomics

DOI:  https://doi.org/10.3390/biomedicines10030704
Cell Metab. 2022 Mar 15. pii: S1550-4131(22)00087-0. [Epub ahead of print]

The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming.

Sophia M Hochrein, Hao Wu, Miriam Eckstein, Laura Arrigoni, Josip S Herman, Fabian Schumacher, Christian Gerecke, Mathias Rosenfeldt, Dominic Grün, Burkhard Kleuser, Georg Gasteiger, Wolfgang Kastenmüller, Bart Ghesquière, Jan Van den Bossche, E Dale Abel, Martin Vaeth.

  Metabolic reprogramming is a hallmark of activated T cells. The switch from oxidative phosphorylation to aerobic glycolysis provides energy and intermediary metabolites for the biosynthesis of macromolecules to support clonal expansion and effector function. Here, we show that glycolytic reprogramming additionally controls inflammatory gene expression via epigenetic remodeling. We found that the glucose transporter GLUT3 is essential for the effector functions of Th17 cells in models of autoimmune colitis and encephalomyelitis. At the molecular level, we show that GLUT3-dependent glucose uptake controls a metabolic-transcriptional circuit that regulates the pathogenicity of Th17 cells. Metabolomic, epigenetic, and transcriptomic analyses linked GLUT3 to mitochondrial glucose oxidation and ACLY-dependent acetyl-CoA generation as a rate-limiting step in the epigenetic regulation of inflammatory gene expression. Our findings are also important from a translational perspective because inhibiting GLUT3-dependent acetyl-CoA generation is a promising metabolic checkpoint to mitigate Th17-cell-mediated inflammatory diseases.

Keywords:  ACLY; ATP-citrate lyase; GLUT1; GLUT3; Th17 cells; acetyl-CoA; glucose metabolism; glycolysis; histone acetylation; immunometabolism

DOI:  https://doi.org/10.1016/j.cmet.2022.02.015
Immunology. 2022 Mar 23.

1,25-dihydroxyvitamin D3 suppresses CD4+ T cell effector functionality by inhibition of glycolysis.

E L Bishop, N Gudgeon, G Mackie, D Chauss, J Roberts, D A Tennant, K M Maslowski, B Afzali, M Hewison, S Dimeloe.

  In CD4+ T helper cells, the active form of vitamin D3 , 1,25-dihydroxyvitamin D3 (1,25D) suppresses production of inflammatory cytokines, including interferon-gamma (IFN-γ), but the mechanisms for this are not yet fully defined. In innate immune cells, response to 1,25D has been linked to metabolic reprogramming. It is unclear whether 1,25D has similar effects on CD4+ T cells, although it is known that antigen stimulation of these cells promotes an anabolic metabolic phenotype, characterised by high rates of aerobic glycolysis to support clonal expansion and effector cytokine expression. Here, we performed in-depth analysis of metabolic capacity and pathway usage, employing extracellular flux and stable isotope-based tracing approaches, in CD4+ T cells treated with 1,25D. We report that 1,25D significantly decreases rates of aerobic glycolysis in activated CD4+ T cells, whilst exerting a lesser effect on mitochondrial glucose oxidation. This is associated with transcriptional repression of Myc, but not repression of mTOR activity under these conditions. Consistent with the modest effect of 1,25D on mitochondrial activity, it also did not impact CD4+ T cell mitochondrial mass or membrane potential. Finally, we demonstrate that inhibition of aerobic glycolysis by 1,25D substantially contributes to its immune-regulatory capacity in CD4+ T cells, since the suppression of IFN-γ expression was significantly blunted in the absence of aerobic glycolysis. This article is protected by copyright. All rights reserved.

Keywords:  T cell; glycolysis; immunometabolism; metabolism; vitamin D

DOI:  https://doi.org/10.1111/imm.13472
Nature. 2022 Mar 23.

Androgen receptor activity in T cells limits checkpoint blockade efficacy.

Xiangnan Guan, Fanny Polesso, Chaojie Wang, Archana Sehrawat, Reed M Hawkins, Susan E Murray, George V Thomas, Breanna Caruso, Reid F Thompson, Mary A Wood, Christina Hipfinger, Scott A Hammond, Julie N Graff, Zheng Xia, Amy E Moran.

Immune checkpoint blockade has revolutionized the field of oncology, inducing durable anti-tumour immunity in solid tumours. In patients with advanced prostate cancer, immunotherapy treatments have largely failed1-5. Androgen deprivation therapy is classically administered in these patients to inhibit tumour cell growth, and we postulated that this therapy also affects tumour-associated T cells. Here we demonstrate that androgen receptor (AR) blockade sensitizes tumour-bearing hosts to effective checkpoint blockade by directly enhancing CD8 T cell function. Inhibition of AR activity in CD8 T cells prevented T cell exhaustion and improved responsiveness to PD-1 targeted therapy via increased IFNγ expression. AR bound directly to Ifng and eviction of AR with a small molecule significantly increased cytokine production in CD8 T cells. Together, our findings establish that T cell intrinsic AR activity represses IFNγ expression and represents a novel mechanism of immunotherapy resistance.

DOI: https://doi.org/10.1038/s41586-022-04522-6
Immun Ageing. 2022 Mar 23. 19(1): 16

Telomerase deficiency reflects age-associated changes in CD4+ T cells.

Diana M Matthe, Oana-Maria Thoma, Tobias Sperka, Markus F Neurath, Maximilian J Waldner.

   BACKGROUND: Amongst other systemic changes, aging leads to an immune dysfunction. On the molecular level, a hallmark of aging is telomere shortening. The functional relevance of telomerase, an enzyme capable of elongating telomeres in T cells upon antigen stimulation, is not fully understood. Studying the impact of telomere shortening on CD4+ T cells and especially Th1 effector function can provide a better understanding on immune dysfunctions in elderly.
RESULTS: We investigated T cell numbers and differentiation in telomerase-deficient (mTerc-/-) mice under steady-state conditions and the functional role of telomerase in CD4+ T cells using in vitro stimulation and Th1 polarization protocols by comparing T cells from mTerc-/- and control mice. We report reduced relative CD4+ T cell numbers in blood and secondary lymphoid organs and a relative decline in the naïve T cell population in thymus, blood and spleen of mTerc-/- mice compared to control mice. Importantly, after in vitro polarization, mTerc-/- G3 CD4+ T cells showed higher numbers of IFNγ-producing cells and reduced expression of CD28. Notably, telomerase-deficient T cells were more susceptible to inhibition of Th1 polarization by IL-6 in vitro. These results demonstrate that telomerase deficiency recapitulates several changes of CD4+ T cells seen in aged humans regarding the naïve T cell population, expression of CD28 and cytokine production.
CONCLUSION: Our data suggest that telomere shortening could play a key role in the aging of T cell immunity, with clinical implications for immune diseases and tumor development and that mTerc-/- mice are a suitable model to study aging-related defects of adaptive immunity.

Keywords:  Aging; CD4-positive T-lymphocytes; Telomerase; Telomere shortening; Th1 cells

DOI:  https://doi.org/10.1186/s12979-022-00273-0
Cancer Cell. 2022 Mar 15. pii: S1535-6108(22)00118-0. [Epub ahead of print]

CD8+ T cells PUF(A)ing the flames of cancer ferroptotic cell death.

José Pedro Friedmann Angeli, Thamara Nishida Xavier da Silva, Bastian Schilling.

In this issue of Cancer Cell, Liao et al. demonstrate that CD8+ T cell-secreted interferon-gamma (IFN-γ) rewires cancer cell lipid metabolism via the enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4). ACSL4 activates polyunsaturated fatty acids and sensitizes cancer cells to ferroptosis in immunotherapy-relevant settings. These findings provide insights into how the metabolic and immune milieu could be used to promote ferroptosis.

DOI: https://doi.org/10.1016/j.ccell.2022.03.003
J Immunother Cancer. 2022 Mar;pii: e003477. [Epub ahead of print]10(3):

1α,25(OH)2D3 reverses exhaustion and enhances antitumor immunity of human cytotoxic T cells.

Peng Li, Xinhai Zhu, Guangchao Cao, Ruan Wu, Ke Li, Wenhui Yuan, Biyun Chen, Guodong Sun, Xichun Xia, Hua Zhang, Xiao Wang, Zhinan Yin, Ligong Lu, Yunfei Gao.

   BACKGROUND: Epidemiological surveys have revealed that low serum vitamin D level was correlated with increased risk of tumors. Dysfunctional T cells in patients with tumor are characterized as exhausted with high levels of immune checkpoint receptors (ICRs). However, whether the reduced level of vitamin D in patients with cancer correlates with cytotoxic T-cell exhaustion is unknown.
METHODS: Periphery blood samples from 172 patients with non-small cell lung cancer (NSCLC) were prospectively collected. Patients with NSCLC received one course of intravenous docetaxel (75 mg/m2) followed by treatment with or without rocaltrol at a dose of 0.5-2.0 µg/day for total of 3 weeks. We performed phenotypical and functional analysis of T-cell through flow cytometry. Vitamin D receptor (VDR) knockout and overexpression CD8+ and Vδ2+ T cells were constructed using Cas9-gRNA targeted and overexpressing approaches to identify 1α,25(OH)2D3/VDR-mediated transcription regulation for ICRs or antitumor activity in T cells.
RESULTS: We show that serum level of vitamin D is negatively correlated with expression of programmed cell death-1 (PD-1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), but positively correlated with CD28 expression on CD8+ and Vγ9Vδ2+ T cells in patients with NSCLC. 1α,25(OH)2D3, the active form of vitamin D, promotes the nuclear translocation of VDR, which binds to the promoter region of Pdcd1, Tim3, and Tigit genes and inhibits their expression. Besides, 1α,25(OH)2D3 pretreatment also promotes the methylation of CpG island in the promoter region of the Pdcd1 gene and increases H3K27 acetylation at the promoter region of the Cd28 gene, which leads to surface PD-1 downregulation and CD28 upregulation, respectively. We further reveal that VDR-mediated Ca2+ influx enhanced expression of Th1 cytokines via T-cell receptor activation. Functionally, 1α,25(OH)2D3 pretreated CD8+ T cells or Vγ9Vδ2+ T cells showed increased Th1 cytokine production and enhanced antitumor immunity. Finally, oral 1α,25(OH)2D3 could also decrease expression of PD-1, Tim-3, TIGIT and increase expression of CD28, resulting in cytokine production (associated with antitumor immunity) by cytotoxic T cells of patients with NSCLC.
CONCLUSIONS: Our findings uncover the pleiotropic effects of 1α,25(OH)2D3 in rescuing the exhausted phenotype of human cytotoxic T cells in patients with tumor and in promoting their antitumor immunity.
TRIAL REGISTRATION NUMBER: ChiCTR2100051135.

Keywords:  costimulatory and inhibitory T-cell receptors; immunity; immunotherapy; innate; translational medical research

DOI:  https://doi.org/10.1136/jitc-2021-003477
Nat Commun. 2022 Mar 25. 13(1): 1606

CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity.

Julia Joung, Paul C Kirchgatterer, Ankita Singh, Jang H Cho, Suchita P Nety, Rebecca C Larson, Rhiannon K Macrae, Rebecca Deasy, Yuen-Yi Tseng, Marcela V Maus, Feng Zhang.

The cellular processes that govern tumor resistance to immunotherapy remain poorly understood. To gain insight into these processes, here we perform a genome-scale CRISPR activation screen for genes that enable human melanoma cells to evade cytotoxic T cell killing. Overexpression of four top candidate genes (CD274 (PD-L1), MCL1, JUNB, and B3GNT2) conferred resistance in diverse cancer cell types and mouse xenografts. By investigating the resistance mechanisms, we find that MCL1 and JUNB modulate the mitochondrial apoptosis pathway. JUNB encodes a transcription factor that downregulates FasL and TRAIL receptors, upregulates the MCL1 relative BCL2A1, and activates the NF-κB pathway. B3GNT2 encodes a poly-N-acetyllactosamine synthase that targets >10 ligands and receptors to disrupt interactions between tumor and T cells and reduce T cell activation. Inhibition of candidate genes sensitized tumor models to T cell cytotoxicity. Our results demonstrate that systematic gain-of-function screening can elucidate resistance pathways and identify potential targets for cancer immunotherapy.

DOI: https://doi.org/10.1038/s41467-022-29205-8
Vitam Horm. 2022 ;pii: S0083-6729(22)00014-0. [Epub ahead of print]119 299-324

Telomere length and vitamin B12.

Guruvaiah Praveen, Mudili Sivaprasad, G Bhanuprakash Reddy.

  Telomeres are non-coding nucleoprotein structures consisting of a highly conserved tandem repeat DNA sequence that caps the ends of chromosomes in eukaryotes. Telomeres confer chromosomal stability, protect the genome from nucleolytic degradation, avoid aberrant recombination and improper repair, and prevent random fusion of chromosomes. The end-replication problem results in telomere shortening with every cell division, eventually leading to cellular senescence and aging. Telomere length (TL) is thereby an ideal candidate for "biological aging." Telomeres possess guanine-rich repeats, which are highly susceptible to oxidative stress. Epidemiological studies have indicated the association of telomere attrition with mortality and various age-related diseases. Micronutrients comprising vitamins and minerals act as potential modulators of stress and can influence TL. Research has indicated that vitamin B12 (B12) regulates oxidative stress and maintains genomic stability, thereby influencing telomere integrity and cellular aging. The deficiency of B12 leads to elevated levels of homocysteine, which reduces the methylation potential and increases oxidative stress, thereby compromising the TL. Telomere shortening and mitochondrial dysfunction are independently linked to aging. However, they are connected through telomerase reverse transcriptase activity, which regulates mitochondrial biogenesis. Further, experimental evidence indicated the positive association of B12 with relative TL and mitochondrial DNA copy number, an indirect index of mitochondrial biogenesis. The present chapter provides some insights into the role of B12 in influencing TL. Exploring their association might open new avenues to understand the pathophysiology of aging and age-related diseases.

Keywords:  8-Oxo-G; Aging; Homocysteine; Methylation; Mitochondrial DNA copy number oxidative stress; Telomerase; Telomere length; Vitamin B12

DOI:  https://doi.org/10.1016/bs.vh.2022.01.014
Int J Mol Sci. 2022 Mar 21. pii: 3374. [Epub ahead of print]23(6):

CD8+ T Cell Senescence: Lights and Shadows in Viral Infections, Autoimmune Disorders and Cancer.

Valentina Tedeschi, Giorgia Paldino, Martina Kunkl, Marino Paroli, Rosa Sorrentino, Loretta Tuosto, Maria Teresa Fiorillo.

  CD8+ T lymphocytes are a heterogeneous class of cells that play a crucial role in the adaptive immune response against pathogens and cancer. During their lifetime, they acquire cytotoxic functions to ensure the clearance of infected or transformed cells and, in addition, they turn into memory lymphocytes, thus providing a long-term protection. During ageing, the thymic involution causes a reduction of circulating T cells and an enrichment of memory cells, partially explaining the lowering of the response towards novel antigens with implications in vaccine efficacy. Moreover, the persistent stimulation by several antigens throughout life favors the switching of CD8+ T cells towards a senescent phenotype contributing to a low-grade inflammation that is a major component of several ageing-related diseases. In genetically predisposed young people, an immunological stress caused by viral infections (e.g., HIV, CMV, SARS-CoV-2), autoimmune disorders or tumor microenvironment (TME) could mimic the ageing status with the consequent acceleration of T cell senescence. This, in turn, exacerbates the inflamed conditions with dramatic effects on the clinical progression of the disease. A better characterization of the phenotype as well as the functions of senescent CD8+ T cells can be pivotal to prevent age-related diseases, to improve vaccine strategies and, possibly, immunotherapies in autoimmune diseases and cancer.

Keywords:  CD28− CD57+ CD8+ T cells; CMV; HIV; SARS-CoV-2; autoimmune disease; cancer; immune-senescence; infection; inflammaging

DOI:  https://doi.org/10.3390/ijms23063374
J Clin Invest. 2022 Mar 22. pii: e149571. [Epub ahead of print]

Gut-derived bacterial toxins impair memory CD4 T-cell mitochondrialfunction in HIV-1infection.

Brian Ferrari, Amanda Cabral Da Silva, Ken H Liu, Evgeniya V Saidakova, Larisa B Korolevskaya, Konstantin V Shmagel, Carey Shive, Gabriela Pacheco Sanchez, Mauricio Retuerto, Ashish Arunkumar Sharma, Khader Ghneim, Laura Noel-Romas, Benigno Rodriguez, Mahmoud A Ghannoum, Peter P Hunt, Steven G Deeks, Adam D Burgener, Dean P Jones, Mirela A Dobre, Vincent C Marconi, Rafick-Pierre Sekaly, Souheil-Antoine Younes.

  People living with HIV (PLWH) who are Immune Non-Responders (INR) persons are at greater risk of comorbidity and mortality than are Immune Responders (IR) who restore their CD4 T cells count (IR) after anti-retroviral therapy (ART). INR have low CD4-T cell counts (<350 c/ul), heightened systemic inflammation, and increased CD4-T cell cycling (Ki67+). Here we report the findings that memory CD4-T cells and plasma samples of INR from several cohorts are enriched in gut-derived bacterial solutes (GDBS) p-cresol-sulfate (PCS) and indoxyl sulfate (IS) that both negatively correlated with CD4-T cell counts. In vitro PCS or IS blocked CD4-T cell proliferation, induced apoptosis, and diminished the expression of mitochondrial proteins. Electron microscopy imaging (EMI) revealed perturbations of mitochondria networks similar to those found in INR following incubation of healthy memory CD4-T cells with PCS. Using the bacterial 16S rDNA, INR stool samples were found enriched with proteolytic bacterial genera that metabolize tyrosine and phenylalanine amino acids to produce PCS. We propose that toxic solutes from the gut bacterial flora may impair CD4-T cell recovery during ART and may contribute to CD4-T cell lymphopenia characteristic of INR.

Keywords:  AIDS/HIV; Apoptosis; Infectious disease; Mitochondria; T cell development

DOI:  https://doi.org/10.1172/JCI149571