bims-imseme 2023-12-17 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2023–12–17
27 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Metabolic plasticity of T cell fate decision.
OCA-B promotes autoimmune demyelination through control of stem-like CD4 + T cells.
Re-"Formate" T-cell Antitumor Responses.
Intracellular K+ Limits T-cell Exhaustion and Preserves Antitumor Function.
The effect of metformin on senescence of T lymphocytes.
Stat5 opposes the transcription factor Tox and rewires exhausted CD8+ T cells toward durable effector-like states during chronic antigen exposure.
Trans-vaccenic Acid Reprograms CD8+ T Cells and Enhances Antitumor Immunity.
Antigen exposure reshapes chromatin architecture in central memory CD8+ T cells and imprints enhanced recall capacity.
Stat5a sobers up inTOXicated T cells.
The expanding Pandora's toolbox of CD8+T cell: from transcriptional control to metabolic firing.
CD8+ T Cells Keep Their (K+)urrency for Function.
T cell-mediated curation and restructuring of tumor tissue coordinates an effective immune response.
Comment on "An Injectable Hydrogel to Modulate T Cells for Cancer Immunotherapy".
Clonal expansion of CD8+ T cells in aged mice linked to pro-atherogenic phenotype.
NADPH Oxidase 2-Derived Reactive Oxygen Species Promote CD8+ T Cell Effector Function.
Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence.
The ER stress sensor IRE1 interacts with STIM1 to promote store-operated calcium entry, T cell activation, and muscular differentiation.
Terminally differentiated effector memory T cells associate with cognitive and AD-related biomarkers in an aging-based community cohort.
SHP-1 Regulates CD8+ T Cell Effector Function but Plays a Subtle Role with SHP-2 in T Cell Exhaustion Due to a Stage-Specific Nonredundant Functional Relay.
CD8+ T cells in brain injury and neurodegeneration.
Glutaminase inhibition as potential cancer therapeutics: current status and future applications.
Quantitative proteomics of tissue infiltrating T cells from CRC patients identified Lipocalin-2 induces T cell apoptosis and promotes tumor cell proliferation by iron efflux.
Cancer CD39 drives metabolic adaption and mal-differentiation of CD4+ T cells in patients with non-small-cell lung cancer.
Oleic acid availability impacts thymocyte preprogramming and subsequent peripheral Treg cell differentiation.
Sicilian semi- and supercentenarians: age-related Tγδ cell immunophenotype contributes to longevity trait definition.
Spatial metabolic patterns.
Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion.

Chin Med J (Engl). 2023 Dec 12.

Metabolic plasticity of T cell fate decision.

Xiaoli Pan, Jiajia Wang, Lianjun Zhang, Guideng Li, Bo Huang.

ABSTRACT: The efficacy of adaptive immune responses in cancer treatment relies heavily on the state of the T cells. Upon antigen exposure, T cells undergo metabolic reprogramming, leading to the development of functional effectors or memory populations. However, within the tumor microenvironment (TME), metabolic stress impairs CD8+ T cell anti-tumor immunity, resulting in exhausted differentiation. Recent studies suggest that targeting T cell metabolism could offer promising therapeutic opportunities to enhance T cell immunotherapy. In this review, we provide a comprehensive summary of the intrinsic and extrinsic factors necessary for metabolic reprogramming during the development of effector and memory T cells in response to acute and chronic inflammatory conditions. Furthermore, we delved into the different metabolic switches that occur during T cell exhaustion, exploring how prolonged metabolic stress within the TME triggers alterations in cellular metabolism and the epigenetic landscape that contribute to T cell exhaustion, ultimately leading to a persistently exhausted state. Understanding the intricate relationship between T cell metabolism and cancer immunotherapy can lead to the development of novel approaches to improve the efficacy of T cell-based treatments against cancer.

DOI: https://doi.org/10.1097/CM9.0000000000002989
bioRxiv. 2023 Nov 30. pii: 2023.11.29.569210. [Epub ahead of print]

OCA-B promotes autoimmune demyelination through control of stem-like CD4 + T cells.

Erik P Hughes, Amber Syage, Elnaz Mirzaei Mehrabad, Thomas E Lane, Benjamin T Spike, Dean Tantin.

Stem-like T cell populations can selectively promote autoimmunity, but the activities that sustain these populations are incompletely understood. Here, we show that T cell-intrinsic loss of the transcription cofactor OCA-B protects mice from experimental autoimmune encephalomyelitis (EAE) while preserving responses to infection. In EAE models driven by antigen re-encounter, OCA-B deletion eliminates CNS infiltration, proinflammatory cytokine production and clinical disease. OCA-B-expressing CD4 + T cells within the CNS of mice with EAE display a memory phenotype and preferentially confer disease. In a relapsing-remitting EAE model, OCA-B T cell-deficiency specifically protects mice from relapse. During remission, OCA-B promotes the expression of Tcf7 , Slamf6 , and Sell in proliferating T cell populations. At relapse, OCA-B loss results in both the accumulation of an immunomodulatory CD4 + T cell population expressing Ccr9 and Bach2 , and the loss of effector gene expression from Th17 cells. These results identify OCA-B as a driver of pathogenic stem-like T cells.

DOI: https://doi.org/10.1101/2023.11.29.569210
Cancer Discov. 2023 Dec 12. 13(12): 2507-2509

Re-"Formate" T-cell Antitumor Responses.

Mei-Chun Lin, Sofie Hedlund Moller, Ping-Chih Ho.

SUMMARY: Rowe and colleagues discover that one-carbon (1C) metabolism rewiring occurs upon T-cell activation to support proliferation and cytolytic activity in CD8+ T cells and that supplementation of 1C donor formate rescues the dysfunctional T cells and their responsiveness to anti-PD-1 in selective tumor-infiltrated T-cell subsets. This finding represents an attractive strategy to overcome a metabolic vulnerability in the tumor microenvironment and improve the efficacy of immune checkpoint blockade. See related article by Rowe et al., p. 2566 (8).

DOI: https://doi.org/10.1158/2159-8290.CD-23-1059
Cancer Immunol Res. 2023 Dec 08. OF1-OF12

Intracellular K+ Limits T-cell Exhaustion and Preserves Antitumor Function.

Camille Collier, Kelly Wucherer, Matthew McWhorter, Chelsea Jenkins, Alexandra Bartlett, Rahul Roychoudhuri, Robert Eil.

T cells are often compromised within cancers, allowing disease progression. We previously found that intratumoral elevations in extracellular K+, related to ongoing cell death, constrained CD8+ T-cell Akt-mTOR signaling and effector function. To alleviate K+-mediated T-cell dysfunction, we pursued genetic means to lower intracellular K+. CD8+ T cells robustly and dynamically express the Na+/K+ ATPase, among other K+ transporters. CRISPR-Cas9-mediated disruption of the Atp1a1 locus lowered intracellular K+ and elevated the resting membrane potential (i.e., Vm, Ψ). Despite compromised Ca2+ influx, Atp1a1-deficient T cells harbored tonic hyperactivity in multiple signal transduction cascades, along with a phenotype of exhaustion in mouse and human CD8+ T cells. Provision of exogenous K+ restored intracellular levels in Atp1a1-deficient T cells and prevented damaging levels of reactive oxygen species (ROS), and both antioxidant treatment and exogenous K+ prevented Atp1a1-deficient T-cell exhaustion in vitro. T cells lacking Atp1a1 had compromised persistence and antitumor activity in a syngeneic model of orthotopic murine melanoma. Translational application of these findings will require balancing the beneficial aspects of intracellular K+ with the ROS-dependent nature of T-cell effector function. See related Spotlight by Banuelos and Borges da Silva.

DOI: https://doi.org/10.1158/2326-6066.CIR-23-0319
Immun Ageing. 2023 Dec 12. 20(1): 73

The effect of metformin on senescence of T lymphocytes.

Jia Yang, Hai-Cheng Liu, Jian-Qing Zhang, Jian-Yong Zou, Xin Zhang, Wo-Ming Chen, Yong Gu, Hai Hong.

   BACKGROUND: Immunosenescence occurs as people age, leading to an increased incidence of age-related diseases. The number of senescent T cells also rises with age. T cell senescence and immune response dysfunction can result in a decline in immune function, especially in anti-tumor immune responses. Metformin has been shown to have various beneficial effects on health, such as lowering blood sugar levels, reducing the risk of cancer development, and slowing down the aging process. However, the immunomodulatory effects of metformin on senescent T cells still need to be investigated.
METHODS: PBMCs isolation from different age population (n = 88); Flow Cytometry is applied to determine the phenotypic characterization of senescent T lymphocytes; intracellular staining is applied to determine the function of senescent T cells; Enzyme-Linked Immunosorbent Assay (ELISA) is employed to test the telomerase concentration. The RNA-seq analysis of gene expression associated with T cell senescence.
RESULTS: The middle-aged group had the highest proportion of senescent T cells. We found that metformin could decrease the number of CD8 + senescent T cells. Metformin affects the secretion of SASP, inhibiting the secretion of IFN-γ in CD8 + senescent T cells. Furthermore, metformin treatment restrained the production of the proinflammatory cytokine IL-6 in lymphocytes. Metformin had minimal effects on Granzyme B secretion in senescent T cells, but it promoted the production of TNF-α in senescent T cells. Additionally, metformin increased the concentration of telomerase and the frequency of undifferentiated T cells. The results of RNA-seq showed that metformin promoted the expression of genes related to stemness and telomerase activity, while inhibiting the expression of DNA damage-associated genes.
CONCLUSION: Our findings reveal that metformin could inhibit T cell senescence in terms of cell number, effector function, telomerase content and gene expression in middle-aged individuals, which may serve as a promising approach for preventing age-related diseases in this population.

Keywords:  Inhibition; Metformin; SASP; Senescent T cell

DOI:  https://doi.org/10.1186/s12979-023-00394-0
Immunity. 2023 Dec 12. pii: S1074-7613(23)00487-9. [Epub ahead of print]56(12): 2699-2718.e11

Stat5 opposes the transcription factor Tox and rewires exhausted CD8+ T cells toward durable effector-like states during chronic antigen exposure.

Jean-Christophe Beltra, Mohamed S Abdel-Hakeem, Sasikanth Manne, Zhen Zhang, Hua Huang, Makoto Kurachi, Leon Su, Lora Picton, Shin Foong Ngiow, Yuki Muroyama, Valentina Casella, Yinghui J Huang, Josephine R Giles, Divij Mathew, Jonathan Belman, Max Klapholz, Hélène Decaluwe, Alexander C Huang, Shelley L Berger, K Christopher Garcia, E John Wherry.

  Rewiring exhausted CD8+ T (Tex) cells toward functional states remains a therapeutic challenge. Tex cells are epigenetically programmed by the transcription factor Tox. However, epigenetic remodeling occurs as Tex cells transition from progenitor (Texprog) to intermediate (Texint) and terminal (Texterm) subsets, suggesting development flexibility. We examined epigenetic transitions between Tex cell subsets and revealed a reciprocally antagonistic circuit between Stat5a and Tox. Stat5 directed Texint cell formation and re-instigated partial effector biology during this Texprog-to-Texint cell transition. Constitutive Stat5a activity antagonized Tox and rewired CD8+ T cells from exhaustion to a durable effector and/or natural killer (NK)-like state with superior anti-tumor potential. Temporal induction of Stat5 activity in Tex cells using an orthogonal IL-2:IL2Rβ-pair fostered Texint cell accumulation, particularly upon PD-L1 blockade. Re-engaging Stat5 also partially reprogrammed the epigenetic landscape of exhaustion and restored polyfunctionality. These data highlight therapeutic opportunities of manipulating the IL-2-Stat5 axis to rewire Tex cells toward more durably protective states.

Keywords:  CD8(+) T cell; IL-2; PD-1 blockade; Stat5; Tex intermediate; Tox; epigenetic reprogramming; exhaustion; orthogonal IL-2:IL2Rβ

DOI:  https://doi.org/10.1016/j.immuni.2023.11.005
Cancer Discov. 2023 Dec 08. OF1

Trans-vaccenic Acid Reprograms CD8+ T Cells and Enhances Antitumor Immunity.

Trans-vaccenic acid (TVA) enhances antitumor immunity by promoting CD8+ T-cell accumulation and function.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2023-192
Proc Natl Acad Sci U S A. 2023 Dec 19. 120(51): e2313476120

Antigen exposure reshapes chromatin architecture in central memory CD8+ T cells and imprints enhanced recall capacity.

Shaoqi Zhu, Jia Liu, Vanita Patel, Xiuyi Zhao, Weiqun Peng, Hai-Hui Xue.

  CD62L+ central memory CD8+ T (TCM) cells provide enhanced protection than naive cells; however, the underlying mechanism, especially the contribution of higher-order genomic organization, remains unclear. Systematic Hi-C analyses reveal that antigen-experienced CD8+ T cells undergo extensive rewiring of chromatin interactions (ChrInt), with TCM cells harboring specific interaction hubs compared with naive CD8+ T cells, as observed at cytotoxic effector genes such as Ifng and Tbx21. TCM cells also acquire de novo CTCF (CCCTC-binding factor) binding sites, which are not only strongly associated with TCM-specific hubs but also linked to increased activities of local gene promoters and enhancers. Specific ablation of CTCF in TCM cells impairs rapid induction of genes in cytotoxic program, energy supplies, transcription, and translation by recall stimulation. Therefore, acquisition of CTCF binding and ChrInt hubs by TCM cells serves as a chromatin architectural basis for their transcriptomic dynamics in primary response and for imprinting the code of "recall readiness" against secondary challenge.

Keywords:  3D genome organization; CTCF; central memory CD8 T cells; chromatin interaction; recall capacity

DOI:  https://doi.org/10.1073/pnas.2313476120
Immunity. 2023 Dec 12. pii: S1074-7613(23)00495-8. [Epub ahead of print]56(12): 2670-2672

Stat5a sobers up inTOXicated T cells.

Lara V Donhauser, Dietmar Zehn.

Exhausted T cells are largely hampered by epigenetically enforced mechanisms that limit their effector potential. In this issue of Immunity, Beltra et al. found that Stat5 can alter these epigenetic profiles when T cells transition from the Tpex precursor stage into differentiated cells. At this stage, enforced Stat5 expression increases the number of intermediate exhausted T cells and induces durable effector cells with superior anti-tumor activity.

DOI: https://doi.org/10.1016/j.immuni.2023.11.013
J Transl Med. 2023 Dec 11. 21(1): 905

The expanding Pandora's toolbox of CD8+T cell: from transcriptional control to metabolic firing.

Jinghong Wu, Zhendong Lu, Hong Zhao, Mingjun Lu, Qing Gao, Nanying Che, Jinghui Wang, Teng Ma.

  CD8+ T cells are the executor in adaptive immune response, especially in anti-tumor immunity. They are the subset immune cells that are of high plasticity and multifunction. Their development, differentiation, activation and metabolism are delicately regulated by multiple factors. Stimuli from the internal and external environment could remodel CD8+ T cells, and correspondingly they will also make adjustments to the microenvironmental changes. Here we describe the most updated progresses in CD8+ T biology from transcriptional regulation to metabolism mechanisms, and also their interactions with the microenvironment, especially in cancer and immunotherapy. The expanding landscape of CD8+ T cell biology and discovery of potential targets to regulate CD8+ T cells will provide new viewpoints for clinical immunotherapy.

Keywords:  Anti-tumor immunity; CD8+ T cells; Immunotherapy

DOI:  https://doi.org/10.1186/s12967-023-04775-3
Cancer Immunol Res. 2023 Dec 08. OF1

CD8+ T Cells Keep Their (K+)urrency for Function.

Alma Banuelos, Henrique Borges da Silva.

CD8+ T-cell responses are influenced by ion abundance, which can widely vary within the tumor microenvironment. In this issue, Collier and colleagues investigated how intracellular versus extracellular potassium ion (K+) regulates intratumoral CD8+ T cells. They show that, while excessive extracellular K+ induces exhaustion, intracellular K+ is needed for protection from dysfunction. This work shows additional evidence that the regulation of CD8+ T-cell responses depends on a fine balance between intracellular and extracellular metabolite levels. See related article by Collier et al. (2) .

DOI: https://doi.org/10.1158/2326-6066.CIR-23-0961
Cell Rep. 2023 Dec 11. pii: S2211-1247(23)01506-1. [Epub ahead of print]42(12): 113494

T cell-mediated curation and restructuring of tumor tissue coordinates an effective immune response.

John W Hickey, Maximillian Haist, Nina Horowitz, Chiara Caraccio, Yuqi Tan, Andrew J Rech, Marc-Andrea Baertsch, Xavier Rovira-Clavé, Bokai Zhu, Gustavo Vazquez, Graham Barlow, Eran Agmon, Yury Goltsev, John B Sunwoo, Markus Covert, Garry P Nolan.

  Antigen-specific T cells traffic to, are influenced by, and create unique cellular microenvironments. Here we characterize these microenvironments over time with multiplexed imaging in a melanoma model of adoptive T cell therapy and human patients with melanoma treated with checkpoint inhibitor therapy. Multicellular neighborhood analysis reveals dynamic immune cell infiltration and inflamed tumor cell neighborhoods associated with CD8+ T cells. T cell-focused analysis indicates T cells are found along a continuum of neighborhoods that reflect the progressive steps coordinating the anti-tumor immune response. More effective anti-tumor immune responses are characterized by inflamed tumor-T cell neighborhoods, flanked by dense immune infiltration neighborhoods. Conversely, ineffective T cell therapies express anti-inflammatory cytokines, resulting in regulatory neighborhoods, spatially disrupting productive T cell-immune and -tumor interactions. Our study provides in situ mechanistic insights into temporal tumor microenvironment changes, cell interactions critical for response, and spatial correlates of immunotherapy outcomes, informing cellular therapy evaluation and engineering.

Keywords:  CODEX; CP: Cancer; CP: Immunology; Multiplexed tissue imaging; T cell phenotype; T cell therapy; T cells; cancer immunotherapy; checkpoint inhibitor therapy; melanoma; metabolism; spatial biology

DOI:  https://doi.org/10.1016/j.celrep.2023.113494
Small. 2023 Dec 10. e2302812

Comment on "An Injectable Hydrogel to Modulate T Cells for Cancer Immunotherapy".

Liangbin Lin, Sunfu Zhang, Wenyong Yang.

  Recent clinical successes of immune checkpoint blockade (ICB) therapies represents a milestone as a novel anti-tumor strategy beyond surgery, radiotherapy, chemotherapy, and targeted therapy in cancer therapy. T cells, especially CD8+ T cells, play crucial roles in anti-tumor immune responses. However, most T cells in the tumor microenvironment express high inhibitory receptors, such as PD-1, TIM-3, and LAG-3, and decreased T cell response in response to stimuli. Applying ICB therapies, such as anti-PD-1, promotes T cell activation and increases cytotoxic T lymphocyte (CTL) response, leading to the enhanced anti-tumor immune response in patients with malignancy. Therefore, studies aimed to define novel targets that can restrain T cell terminal exhaustion are urgently required to provide new strategies for patients resistant to immunotherapy. The previously published study by Zhang et al. (An Injectable Hydrogel to Modulate T Cells for Cancer Immunotherapy, https://doi.org/10.1002/smll.202202663) introduces a new type of injectable hydrogel that can regulate the function of T cells, thereby improving their effectiveness in cancer immunotherapy. However, it remains to be discussed for its conclusion, as the flow cell assay of this article may not be proper.

Keywords:  CD8+ T cells; T cell exhuastion; Tumor Infiltrating Lymphocytes; tumor immunology

DOI:  https://doi.org/10.1002/smll.202302812
Nat Rev Cardiol. 2023 Dec 08.

Clonal expansion of CD8+ T cells in aged mice linked to pro-atherogenic phenotype.

Karina Huynh.

DOI: https://doi.org/10.1038/s41569-023-00981-0
J Immunol. 2023 Dec 11. pii: ji2200691. [Epub ahead of print]

NADPH Oxidase 2-Derived Reactive Oxygen Species Promote CD8+ T Cell Effector Function.

Jing Chen, Chao Liu, Anna V Chernatynskaya, Brittney Newby, Todd M Brusko, Yuan Xu, Jessie M Barra, Nadine Morgan, Christopher Santarlas, Westley H Reeves, Hubert M Tse, Jennifer W Leiding, Clayton E Mathews.

Oxidants participate in lymphocyte activation and function. We previously demonstrated that eliminating the activity of NADPH oxidase 2 (NOX2) significantly impaired the effectiveness of autoreactive CD8+ CTLs. However, the molecular mechanisms impacting CD8+ T cell function remain unknown. In the present study, we examined the role of NOX2 in both NOD mouse and human CD8+ T cell function. Genetic ablation or chemical inhibition of NOX2 in CD8+ T cells significantly suppressed activation-induced expression of the transcription factor T-bet, the master transcription factor of the Tc1 cell lineage, and T-bet target effector genes such as IFN-γ and granzyme B. Inhibition of NOX2 in both human and mouse CD8+ T cells prevented target cell lysis. We identified that superoxide generated by NOX2 must be converted into hydrogen peroxide to transduce the redox signal in CD8+ T cells. Furthermore, we show that NOX2-generated oxidants deactivate the tumor suppressor complex leading to activation of RheB and subsequently mTOR complex 1. These results indicate that NOX2 plays a nonredundant role in TCR-mediated CD8+ T cell effector function.

DOI: https://doi.org/10.4049/jimmunol.2200691
Aging Cell. 2023 Dec 07. e14060

Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence.

Sophia A Mahoney, Ravinandan Venkatasubramanian, Mary A Darrah, Katelyn R Ludwig, Nicholas S VanDongen, Nathan T Greenberg, Abigail G Longtine, David A Hutton, Vienna E Brunt, Judith Campisi, Simon Melov, Douglas R Seals, Matthew J Rossman, Zachary S Clayton.

  Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related arterial dysfunction, in part, by promoting oxidative stress and inflammation, which reduce the bioavailability of the vasodilatory molecule nitric oxide (NO). In the present study, we assessed the efficacy of fisetin, a natural compound, as a senolytic to reduce vascular cell senescence and SASP factors and improve arterial function in old mice. We found that fisetin decreased cellular senescence in human endothelial cell culture. In old mice, vascular cell senescence and SASP-related inflammation were lower 1 week after the final dose of oral intermittent (1 week on-2 weeks off-1 weeks on dosing) fisetin supplementation. Old fisetin-supplemented mice had higher endothelial function. Leveraging old p16-3MR mice, a transgenic model allowing genetic clearance of p16INK4A -positive senescent cells, we found that ex vivo removal of senescent cells from arteries isolated from vehicle- but not fisetin-treated mice increased endothelium-dependent dilation, demonstrating that fisetin improved endothelial function through senolysis. Enhanced endothelial function with fisetin was mediated by increased NO bioavailability and reduced cellular- and mitochondrial-related oxidative stress. Arterial stiffness was lower in fisetin-treated mice. Ex vivo genetic senolysis in aorta rings from p16-3MR mice did not further reduce mechanical wall stiffness in fisetin-treated mice, demonstrating lower arterial stiffness after fisetin was due to senolysis. Lower arterial stiffness with fisetin was accompanied by favorable arterial wall remodeling. The findings from this study identify fisetin as promising therapy for clinical translation to target excess cell senescence to treat age-related arterial dysfunction.

Keywords:  aging; arterial stiffness; cellular senescence; endothelial function; nutraceutical; vascular dysfunction

DOI:  https://doi.org/10.1111/acel.14060
Cell Rep. 2023 Dec 05. pii: S2211-1247(23)01552-8. [Epub ahead of print]42(12): 113540

The ER stress sensor IRE1 interacts with STIM1 to promote store-operated calcium entry, T cell activation, and muscular differentiation.

Amado Carreras-Sureda, Xin Zhang, Loann Laubry, Jessica Brunetti, Stéphane Koenig, Xiaoxia Wang, Cyril Castelbou, Claudio Hetz, Yong Liu, Maud Frieden, Nicolas Demaurex.

  Store-operated Ca2+ entry (SOCE) mediated by stromal interacting molecule (STIM)-gated ORAI channels at endoplasmic reticulum (ER) and plasma membrane (PM) contact sites maintains adequate levels of Ca2+ within the ER lumen during Ca2+ signaling. Disruption of ER Ca2+ homeostasis activates the unfolded protein response (UPR) to restore proteostasis. Here, we report that the UPR transducer inositol-requiring enzyme 1 (IRE1) interacts with STIM1, promotes ER-PM contact sites, and enhances SOCE. IRE1 deficiency reduces T cell activation and human myoblast differentiation. In turn, STIM1 deficiency reduces IRE1 signaling after store depletion. Using a CaMPARI2-based Ca2+ genome-wide screen, we identify CAMKG2 and slc105a as SOCE enhancers during ER stress. Our findings unveil a direct crosstalk between SOCE and UPR via IRE1, acting as key regulator of ER Ca2+ and proteostasis in T cells and muscles. Under ER stress, this IRE1-STIM1 axis boosts SOCE to preserve immune cell functions, a pathway that could be targeted for cancer immunotherapy.

Keywords:  CP: Cell biology; CP: Immunology; CRISPR screening; CaMPARI; ER stress; IRE1; SOCE; STIM1; T cells; calcium; muscle

DOI:  https://doi.org/10.1016/j.celrep.2023.113540
bioRxiv. 2023 Nov 28. pii: 2023.11.27.568812. [Epub ahead of print]

Terminally differentiated effector memory T cells associate with cognitive and AD-related biomarkers in an aging-based community cohort.

Edric Winford, Jenny Lutshumba, Barbara J Martin, Donna M Wilcock, Gregory A Jicha, Barbara S Nikolajczyk, Ann M Stowe, Adam D Bachstetter.

Background and Purpose: The immune response changes during aging and the progression of Alzheimer's disease (AD) and related dementia (ADRD). Terminally differentiated effector memory T cells (called T EMRA ) are important during aging and AD due to their cytotoxic phenotype and association with cognitive decline. However, it is not clear if the changes seen in T EMRAs are specific to AD-related cognitive decline specifically or are more generally correlated with cognitive decline. This study aimed to examine whether T EMRAs are associated with cognition and plasma biomarkers of AD, neurodegeneration, and neuroinflammation in a community-based cohort of older adults.
Methods: Study participants from a University of Kentucky Alzheimer's Disease Research Center (UK-ADRC) community-based cohort of aging and dementia were used to test our hypothesis. There were 84 participants, 44 women and 40 men. Participants underwent physical examination, neurological examination, medical history, cognitive testing, and blood collection to determine plasma biomarker levels (Aβ42/Aβ40 ratio, total tau, Neurofilament Light chain (Nf-L), Glial Fibrillary Acidic Protein (GFAP)) and to isolate peripheral blood mononuclear cells (PBMCs). Flow cytometry was used to analyze PBMCs from study participants for effector and memory T cell populations, including CD4 + and CD8 + central memory T cells (T CM ), Naïve T cells, effector memory T cells (T EM ), and effector memory CD45RA + T cells (T EMRA ) immune cell markers.
Results: CD8 + T EMRAs were positively correlated with Nf-L and GFAP. We found no significant difference in CD8 + T EMRAs based on cognitive scores and no associations between CD8 + T EMRAs and AD-related biomarkers. CD4 + T EMRAs were associated with cognitive impairment on the MMSE. Gender was not associated with T EMRAs , but it did show an association with other T cell populations.
Conclusion: These findings suggest that the accumulation of CD8 + T EMRAs may be a response to neuronal injury (Nf-L) and neuroinflammation (GFAP) during aging or the progression of AD and ADRD. As our findings in a community-based cohort were not clinically- defined AD participants but included all ADRDs, this suggests that T EMRAs may be associated with changes in systemic immune T cell subsets associated with the onset of pathology.

DOI: https://doi.org/10.1101/2023.11.27.568812
J Immunol. 2023 Dec 13. pii: ji2300462. [Epub ahead of print]

SHP-1 Regulates CD8+ T Cell Effector Function but Plays a Subtle Role with SHP-2 in T Cell Exhaustion Due to a Stage-Specific Nonredundant Functional Relay.

Bowen Hou, Yanyan Hu, Yuzhen Zhu, Xiaocui Wang, Wanyun Li, Jian Tang, Xian Jia, Jiayu Wang, Yu Cong, Minxue Quan, Hongying Yang, Haiping Zheng, Yuzhou Bao, Xiao Lei Chen, Hong-Rui Wang, Bing Xu, Nicholas R J Gascoigne, Guo Fu.

SHP-1 (Src homology region 2 domain-containing phosphatase 1) is a well-known negative regulator of T cells, whereas its close homolog SHP-2 is the long-recognized main signaling mediator of the PD-1 inhibitory pathway. However, recent studies have challenged the requirement of SHP-2 in PD-1 signaling, and follow-up studies further questioned the alternative idea that SHP-1 may replace SHP-2 in its absence. In this study, we systematically investigate the role of SHP-1 alone or jointly with SHP-2 in CD8+ T cells in a series of gene knockout mice. We show that although SHP-1 negatively regulates CD8+ T cell effector function during acute lymphocytic choriomeningitis virus (LCMV) infection, it is dispensable for CD8+ T cell exhaustion during chronic LCMV infection. Moreover, in contrast to the mortality of PD-1 knockout mice upon chronic LCMV infection, mice double deficient for SHP-1 and SHP-2 in CD8+ T cells survived without immunopathology. Importantly, CD8+ T cells lacking both phosphatases still differentiate into exhausted cells and respond to PD-1 blockade. Finally, we found that SHP-1 and SHP-2 suppressed effector CD8+ T cell expansion at the early and late stages, respectively, during chronic LCMV infection.

DOI: https://doi.org/10.4049/jimmunol.2300462
Front Cell Neurosci. 2023 ;17 1281763

CD8+ T cells in brain injury and neurodegeneration.

Zhaolong Zhang, Zhongying Duan, Yu Cui.

  The interaction between the peripheral immune system and the brain is increasingly being recognized as an important layer of neuroimmune regulation and plays vital roles in brain homeostasis as well as neurological disorders. As an important population of T-cell lymphocytes, the roles of CD8+ T cells in infectious diseases and tumor immunity have been well established. Recently, increasing number of complex functions of CD8+ T cells in brain disorders have been revealed. However, an advanced summary and discussion of the functions and mechanisms of CD8+ T cells in brain injury and neurodegeneration are still lacking. Here, we described the differentiation and function of CD8+ T cells, reviewed the involvement of CD8+ T cells in the regulation of brain injury including stroke and traumatic brain injury and neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), and discussed therapeutic prospects and future study goals. Understanding these processes will promote the investigation of T-cell immunity in brain disorders and provide new intervention strategies for the treatment of brain injury and neurodegeneration.

Keywords:  Alzheimer’s disease; CD8+ T cells; Parkinson’s disease; brain injury; ischemic stroke; neurodegeneration; traumatic brain injury

DOI:  https://doi.org/10.3389/fncel.2023.1281763
J Enzyme Inhib Med Chem. 2024 Dec;39(1): 2290911

Glutaminase inhibition as potential cancer therapeutics: current status and future applications.

Rajath Cyriac, Kwangho Lee.

  Alterations in normal metabolic processes are defining features of cancer. Glutamine, an abundant amino acid in the human blood, plays a critical role in regulating several biosynthetic and bioenergetic pathways that support tumour growth. Glutaminolysis is a metabolic pathway that converts glutamine into various metabolites involved in the tricarboxylic acid (TCA) cycle and generates antioxidants that are vital for tumour cell survival. As glutaminase catalyses the initial step of this metabolic pathway, it is of great significance in cancer metabolism and tumour progression. Inhibition of glutaminase and targeting of glutaminolysis have emerged as promising strategies for cancer therapy. This review explores the role of glutaminases in cancer metabolism and discusses various glutaminase inhibitors developed as potential therapies for tumour regression.

Keywords:  GLS; KEAP1 mutation; anticancer; cancer metabolism; glutaminase

DOI:  https://doi.org/10.1080/14756366.2023.2290911
Mol Cell Proteomics. 2023 Dec 08. pii: S1535-9476(23)00202-5. [Epub ahead of print] 100691

Quantitative proteomics of tissue infiltrating T cells from CRC patients identified Lipocalin-2 induces T cell apoptosis and promotes tumor cell proliferation by iron efflux.

Rui Che, Qingsong Wang, Minzhe Li, Jian Shen, Jianguo Ji.

  T cells play the most pivotal roles in anti-tumor immunity, the T cell proteome and the differentially expressed proteins (DEPs) in the tumor immune microenvironment have rarely been identified directly from the clinical samples, especially for tumors that lack effective immunotherapy targets, such as colorectal cancer (CRC). In this study, we analyzed the protein expression pattern of the infiltrating T cells isolated from CRC patients using quantitative proteomics. CD4+ and CD8+ T cells were isolated from clinical samples and labeled by TMT reagents, and the DEPs were quantified by mass spectrometry. The T cell proteome profiling revealed dysfunctions in these tumor-infiltrating T cells. Specifically, anti-tumor immunity was suppressed due to differentially expressed metal ion transporters and immunity regulators. For the first time, Lipocalin-2 (LCN2) was shown to be significantly up-regulated in CD4+ T cells. Quantitative proteomic analysis of LCN2-overexpressed Jurkat cells showed that LCN2 damaged T cells by changes in iron transport. LCN2 induced T cell apoptosis by reducing cellular iron concentration; moreover, the iron that was transported to the tumor microenvironment aided tumor cell proliferation, promoting tumor development. Meanwhile, LCN2 also influenced tumor progression through immune cytokines and cholesterol metabolism. Our results demonstrated that LCN2 has immunosuppressive functions that can promote tumor development; therefore, it is a potential immunotherapy target for CRC.

Keywords:  anti-tumor immunity; colorectal cancer; iron transport; lipocalin-2; tumor-infiltrating T cells

DOI:  https://doi.org/10.1016/j.mcpro.2023.100691
Cell Death Dis. 2023 Dec 08. 14(12): 804

Cancer CD39 drives metabolic adaption and mal-differentiation of CD4+ T cells in patients with non-small-cell lung cancer.

Ying Wang, Mengdi Liu, Lei Zhang, Xiyu Liu, Huiyan Ji, Yan Wang, Jun Gui, Yan Yue, Zhenke Wen.

While ectonucleotidase CD39 is a cancer therapeutic target in clinical trials, its direct effect on T-cell differentiation in human non-small-cell lung cancer (NSCLC) remains unclear. Herein, we demonstrate that human NSCLC cells, including tumor cell lines and primary tumor cells from clinical patients, efficiently drive the metabolic adaption of human CD4+ T cells, instructing differentiation of regulatory T cells while inhibiting effector T cells. Of importance, NSCLC-induced T-cell mal-differentiation primarily depends on cancer CD39, as this can be fundamentally blocked by genetic depletion of CD39 in NSCLC. Mechanistically, NSCLC cells package CD39 into their exosomes and transfer such CD39-containing exosomes into interacting T cells, resulting in ATP insufficiency and AMPK hyperactivation. Such CD39-dependent NSCLC-T cell interaction holds well in patients-derived primary tumor cells and patient-derived organoids (PDOs). Accordingly, genetic depletion of CD39 alone or in combination with the anti-PD-1 immunotherapy efficiently rescues effector T cell differentiation, instigates anti-tumor T cell immunity, and inhibits tumor growth of PDOs. Together, targeting cancer CD39 can correct the mal-differentiation of CD4+ T cells in human NSCLC, providing in-depth insight into therapeutic CD39 inhibitors.

DOI: https://doi.org/10.1038/s41419-023-06336-4
Nat Immunol. 2023 Dec 07.

Oleic acid availability impacts thymocyte preprogramming and subsequent peripheral Treg cell differentiation.

Liangyu Lin, Mingyuan Hu, Qing Li, Liming Du, Li Lin, Yueqing Xue, Fanjun Zheng, Fei Wang, Keli Liu, Yu Wang, Jiayin Ye, Xu Jiang, Xuefeng Wang, Jiaqi Wang, Jingjie Zhai, Benming Liu, Hongzhen Xie, Yanqin You, Jinyong Wang, Xiangyin Kong, Dechun Feng, Douglas R Green, Yufang Shi, Ying Wang.

The nature of activation signals is essential in determining T cell subset differentiation; however, the features that determine T cell subset preference acquired during intrathymic development remain elusive. Here we show that naive CD4+ T cells generated in the mouse thymic microenvironment lacking Scd1, encoding the enzyme catalyzing oleic acid (OA) production, exhibit enhanced regulatory T (Treg) cell differentiation and attenuated development of experimental autoimmune encephalomyelitis. Scd1 deletion in K14+ thymic epithelia recapitulated the enhanced Treg cell differentiation phenotype of Scd1-deficient mice. The dearth of OA permitted DOT1L to increase H3K79me2 levels at the Atp2a2 locus of thymocytes at the DN2-DN3 transition stage. Such epigenetic modification persisted in naive CD4+ T cells and facilitated Atp2a2 expression. Upon T cell receptor activation, ATP2A2 enhanced the activity of the calcium-NFAT1-Foxp3 axis to promote naive CD4+ T cells to differentiate into Treg cells. Therefore, OA availability is critical for preprogramming thymocytes with Treg cell differentiation propensities in the periphery.

DOI: https://doi.org/10.1038/s41590-023-01672-1
Clin Exp Immunol. 2023 Dec 08. pii: uxad132. [Epub ahead of print]

Sicilian semi- and supercentenarians: age-related Tγδ cell immunophenotype contributes to longevity trait definition.

Mattia Emanuela Ligotti, Giulia Accardi, Anna Aiello, Anna Calabrò, Calogero Caruso, Anna Maria Corsale, Francesco Dieli, Marta Di Simone, Serena Meraviglia, Giuseppina Candore.

  The immune system of semi- (from ≥105 to <110 years old) and supercentenarians (≥110 years old), i.e., oldest centenarians, is thought to have characteristics that allow them to reach extreme longevity in relatively healthy status. Thus, we investigated variations of the two principal subsets of Tγδ, Vδ1 and Vδ2, and their functional subsets using the markers defining Tαβ cells, i.e., CD27, CD45RA, in a cohort of 28 women and 26 men (age range 19-110 years), including 11 Long living individuals (from >90 years old to <105 years old), and 8 oldest centenarians (≥105 years old), all of them were previously analysed for Tαβ and NK cell immunophenotypes on the same blood sample collected on recruitment day. Naïve Vδ1 and Vδ2 cells showed an inverse relationship with age, particularly significant for Vδ1 cells. Terminally differentiated T subsets (TEMRA) were significantly increased in Vδ1 but not in Vδ2, with higher values observed in oldest centenarians, although a great heterogeneity was observed. Both naïve and TEMRA Vδ1 and CD8+ Tαβ cells values from our previous study correlated highly significantly, which was not the case for CD4+ and Vδ2. Our findings on γδ TEMRA suggest that these changes are not unfavourable for centenarians, including the oldest ones, supporting the hypothesis that immune ageing should be considered as a differential adaptation rather than a general immune alteration. The increase in TEMRA Vδ1 and CD8+, as well as in NK, would represent immune mechanisms by which the oldest centenarians successfully adapt to a history of insults and achieve longevity.

Keywords:  Tγδ; immune ageing; immunophenotype; longevity; semi-supercentenarians; supercentenarians

DOI:  https://doi.org/10.1093/cei/uxad132
Nat Rev Cancer. 2023 Dec 11.

Spatial metabolic patterns.

Anna Dart.

DOI: https://doi.org/10.1038/s41568-023-00654-7
Nat Commun. 2023 Dec 09. 14(1): 8154

Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion.

Xuemei Gu, Haoran Wei, Caixia Suo, Shengqi Shen, Chuxu Zhu, Liang Chen, Kai Yan, Zhikun Li, Zhenhua Bian, Pinggen Zhang, Mengqiu Yuan, Yingxuan Yu, Jinzhi Du, Huafeng Zhang, Linchong Sun, Ping Gao.

Itaconate is a well-known immunomodulatory metabolite; however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we find that macrophage-derived itaconate promotes HCC by epigenetic induction of Eomesodermin (EOMES)-mediated CD8+ T-cell exhaustion. Our results show that the knockout of immune-responsive gene 1 (IRG1), responsible for itaconate production, suppresses HCC progression. Irg1 knockout leads to a decreased proportion of PD-1+ and TIM-3+ CD8+ T cells. Deletion or adoptive transfer of CD8+ T cells shows that IRG1-promoted tumorigenesis depends on CD8+ T-cell exhaustion. Mechanistically, itaconate upregulates PD-1 and TIM-3 expression levels by promoting succinate-dependent H3K4me3 of the Eomes promoter. Finally, ibuprofen is found to inhibit HCC progression by targeting IRG1/itaconate-dependent tumor immunoevasion, and high IRG1 expression in macrophages predicts poor prognosis in HCC patients. Taken together, our results uncover an epigenetic link between itaconate and HCC and suggest that targeting IRG1 or itaconate might be a promising strategy for HCC treatment.

DOI: https://doi.org/10.1038/s41467-023-43988-4