bims-imseme 2024-09-08 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2024–09–08
eightteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis.
Stem-like CD8+ T cells in cancer.
Aging trajectories of memory CD8 + T cells differ by their antigen specificity.
Glucocorticoid-mediated Suppression of Effector Programming Assists the Memory Transition of Virus-specific CD8+ T Cells.
Metabolic reprogramming and immune evasion: the interplay in the tumor microenvironment.
PD-1 controls differentiation, survival, and TCR affinity evolution of stem-like CD8+ T cells.
The glycolytic reaction PGAM unexpectedly restrains Th17 pathogenicity and Th17-dependent autoimmunity.
Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models.
The transcription regulator ID3 maintains tumor-specific memory CD8+ T cells in draining lymph nodes during tumorigenesis.
IL-18 primes T cells with an antigen-inexperienced memory phenotype for proliferation and differentiation into effector cells through Notch signaling.
Unlocking T cell exhaustion: Insights and implications for CAR-T cell therapy.
Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8+ T cells.
Cellular senescence exacerbates features of aging in the eyes.
Inhibitory co-receptor Lag3 supports Foxp3+ regulatory T cell function by restraining Myc-dependent metabolic programming.
A Unified Atlas of T cell Glycophysiology.
Dietary iron deficiency impairs effector function of memory T cells following influenza infection.
Spermidine controls autophagy during fasting.
An in-depth understanding of the role and mechanisms of T cells in immune organ aging and age-related diseases.

Immunity. 2024 Aug 22. pii: S1074-7613(24)00376-5. [Epub ahead of print]

PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis.

Yu Ping, Jiqi Shan, Haiming Qin, Feng Li, Jiao Qu, Ru Guo, Dong Han, Wei Jing, Yaqing Liu, Jinyan Liu, Zhangnan Liu, Jieyao Li, Dongli Yue, Feng Wang, Liping Wang, Bin Zhang, Bo Huang, Yi Zhang.

  The tumor microenvironment (TME) promotes metabolic reprogramming and dysfunction in immune cells. Here, we examined the impact of the TME on phospholipid metabolism in CD8+ T cells. In lung cancer, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were lower in intratumoral CD8+ T cells than in circulating CD8+ T cells. Intratumoral CD8+ T cells exhibited decreased expression of phospholipid phosphatase 1 (PLPP1), which catalyzes PE and PC synthesis. T cell-specific deletion of Plpp1 impaired antitumor immunity and promoted T cell death by ferroptosis. Unsaturated fatty acids in the TME stimulated ferroptosis of Plpp1-/- CD8+ T cells. Mechanistically, programmed death-1 (PD-1) signaling in CD8+ T cells induced GATA1 binding to the promoter region Plpp1 and thereby suppressed Plpp1 expression. PD-1 blockade increased Plpp1 expression and restored CD8+ T cell antitumor function but did not rescue dysfunction of Plpp1-/- CD8+ T cells. Thus, PD-1 signaling regulates phospholipid metabolism in CD8+ T cells, with therapeutic implications for immunotherapy.

Keywords:  CD8(+) T cell; PD-1 signaling; PLPP1; anti-PD-1 therapy; antitumor immunity; ferroptosis; lipid peroxidation; phospholipid metabolism; tumor microenvironment; unsaturated fatty acid

DOI:  https://doi.org/10.1016/j.immuni.2024.08.003
Front Immunol. 2024 ;15 1426418

Stem-like CD8+ T cells in cancer.

Chelsea Steiner, Nathan Denlinger, Xiaopei Huang, Yiping Yang.

  Stem-like CD8+ T cells (TSL) are a subset of immune cells with superior persistence and antitumor immunity. They are TCF1+ PD-1+ and important for the expansion of tumor specific CD8+ T cells in response to checkpoint blockade immunotherapy. In acute infections, naïve CD8+ T cells differentiate into effector and memory CD8+ T cells; in cancer and chronic infections, persistent antigen stimulation can lead to T cell exhaustion. Recent studies have highlighted the dichotomy between late dysfunctional (or exhausted) T cells (TLD) that are TCF1- PD-1+ and self-renewing TCF1+ PD-1+ TSL from which they derive. TCF1+ TSL cells are considered to have stem cell-like properties akin to memory T cell populations and can give rise to cytotoxic effector and transitory T cell phenotypes (TTE) which mediate tumor control. In this review, we will discuss recent advances made in research on the formation and expansion of TSL, as well as distinct niches required for their differentiation and maintenance in the setting of cancer. We will also discuss potential strategies to generate these cells, with clinical implications for stemness enhancement in vaccine design, immune checkpoint blockade (ICB), and adoptive T cell therapies.

Keywords:  cancer models; chronic viral infection; immune; stem-like CD8 T cells (TSL); tertiary lymphoid structure (TLS); tumor microenvironment (TME)

DOI:  https://doi.org/10.3389/fimmu.2024.1426418
bioRxiv. 2024 Jul 29. pii: 2024.07.26.605197. [Epub ahead of print]

Aging trajectories of memory CD8 + T cells differ by their antigen specificity.

Ines Sturmlechner, Abhinav Jain, Bin Hu, Rohit R Jadhav, Wenqiang Cao, Hirohisa Okuyama, Lu Tian, Cornelia M Weyand, Jörg J Goronzy.

Memory T cells are a highly dynamic and heterogeneous population that is maintained by cytokine-driven homeostatic proliferation interspersed with episodes of antigen-mediated expansion and contraction which affect their functional state and their durability. This heterogeneity complicates studies on the impact of aging on global human memory cells, specifically, it is unclear how aging drives memory T cell dysfunction. Here, we used chronic infection with Epstein-Barr virus (EBV) to assess the influence of age on memory states at the level of antigen-specific CD8 + T cells. We find that in young adults (<40 years), EBV-specific CD8 + T cells assume preferred differentiation states depending on their peptide specificity. By age >65-years, different T cell specificities had undergone largely distinct aging trajectories, which had in common a loss in adaptive and a gain in innate immunity signatures. No evidence was seen for cellular senescence or exhaustion. While naïve/stem-like EBV-specific T cells disappeared with age, T cell diversity of EBV-specific memory cells did not change or even increased. In summary, by controlling for antigen specificity we uncover age-associated shifts in gene expression and TCR diversity that have implications for optimizing vaccination strategies and adoptive T cell therapy.

DOI: https://doi.org/10.1101/2024.07.26.605197
J Immunol. 2024 Aug 30. pii: ji2300513. [Epub ahead of print]

Glucocorticoid-mediated Suppression of Effector Programming Assists the Memory Transition of Virus-specific CD8+ T Cells.

Azeez Tehseen, Dhaneshwar Kumar, Abhishek Dubey, Roman Sarkar, Sudhakar Singh, Sharvan Sehrawat.

We demonstrate the role of signaling via the glucocorticoid receptor, NR3C1, in differentiation of CD8+ T cell memory. Pharmacological inhibition as well as the short hairpin RNA-mediated knockdown of the receptor hindered memory transition and limited the homeostatic turnover of the activated CD8+ T cells. Dexamethasone exposure of CD8+ T cells expanded during a resolving infection with influenza A virus or a γ-herpesvirus promoted conversion of effector cells into memory cells by modulating cellular metabolism and lowering the accumulation of reactive oxygen species. Reduced reactive oxygen species levels in the responding effector cells upregulated Bcl2 and enhanced survival. The generated virus-specific memory CD8+ T cells were efficiently recalled following challenge of animals with a secondary infection to control it better. The memory-enhancing effect was predominantly evident at low doses of dexamethasone. Therefore, controlled glucocorticoid signaling within the effector CD8+ T cells is crucial for optimal memory differentiation.

DOI: https://doi.org/10.4049/jimmunol.2300513
Biomark Res. 2024 Sep 03. 12(1): 96

Metabolic reprogramming and immune evasion: the interplay in the tumor microenvironment.

Haixia Zhang, Shizhen Li, Dan Wang, Siyang Liu, Tengfei Xiao, Wangning Gu, Hongmin Yang, Hui Wang, Minghua Yang, Pan Chen.

  Tumor cells possess complex immune evasion mechanisms to evade immune system attacks, primarily through metabolic reprogramming, which significantly alters the tumor microenvironment (TME) to modulate immune cell functions. When a tumor is sufficiently immunogenic, it can activate cytotoxic T-cells to target and destroy it. However, tumors adapt by manipulating their metabolic pathways, particularly glucose, amino acid, and lipid metabolism, to create an immunosuppressive TME that promotes immune escape. These metabolic alterations impact the function and differentiation of non-tumor cells within the TME, such as inhibiting effector T-cell activity while expanding regulatory T-cells and myeloid-derived suppressor cells. Additionally, these changes lead to an imbalance in cytokine and chemokine secretion, further enhancing the immunosuppressive landscape. Emerging research is increasingly focusing on the regulatory roles of non-tumor cells within the TME, evaluating how their reprogrammed glucose, amino acid, and lipid metabolism influence their functional changes and ultimately aid in tumor immune evasion. Despite our incomplete understanding of the intricate metabolic interactions between tumor and non-tumor cells, the connection between these elements presents significant challenges for cancer immunotherapy. This review highlights the impact of altered glucose, amino acid, and lipid metabolism in the TME on the metabolism and function of non-tumor cells, providing new insights that could facilitate the development of novel cancer immunotherapies.

Keywords:  Immune evasion; Immunotherapy; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1186/s40364-024-00646-1
bioRxiv. 2024 Aug 06. pii: 2024.08.02.606241. [Epub ahead of print]

PD-1 controls differentiation, survival, and TCR affinity evolution of stem-like CD8+ T cells.

Jyh Liang Hor, Edward C Schrom, Abigail Wong-Rolle, Luke Vistain, Wanjing Shang, Qiang Dong, Chen Zhao, Chengcheng Jin, Ronald N Germain.

Stem-like progenitors are a critical subset of cytotoxic T cells that self-renew and give rise to expanded populations of effector cells critical for successful checkpoint blockade immunotherapy. Emerging evidence suggests that the tumor-draining lymph nodes can support the continuous generation of these stem-like cells that replenish the tumor sites and act as a critical source of expanded effector populations, underlining the importance of understanding what factors promote and maintain activated T cells in the stem-like state. Using advanced 3D multiplex immunofluorescence imaging, here we identified antigen-presentation niches in tumor-draining lymph nodes that support the expansion, maintenance, and affinity evolution of a unique population of TCF-1+PD-1+SLAMF6 hi stem-like CD8+ T cells. Our results show that contrary to the prevailing view that persistent TCR signaling drives terminal effector differentiation, prolonged antigen engagement well beyond the initial priming phase sustained the proliferation and self-renewal of these stem-like T cells in vivo . The inhibitory PD-1 pathway plays a central role in this process by mediating the fine-tuning of TCR and co-stimulatory signal input that enables selective expansion of high affinity TCR stem-like clones, enabling them to act as a renewable source of high affinity effector cells. PD-1 checkpoint blockade disrupts this fine tuning of input signaling, leading to terminal differentiation to the effector state or death of the most avid anti-tumor stem-like cells. Our results thus reveal an unexpected relationship between TCR ligand affinity recognition, a key negative feedback regulatory loop, and T cell stemness programming. Furthermore, these findings raise questions about whether anti-PD-1 checkpoint blockade during cancer immunotherapy provides a short-term anti-tumor effect that comes at the cost of diminishing efficacy due to progressive loss of these critical high affinity stem-like precursors.

DOI: https://doi.org/10.1101/2024.08.02.606241
bioRxiv. 2024 Aug 19. pii: 2024.08.18.607992. [Epub ahead of print]

The glycolytic reaction PGAM unexpectedly restrains Th17 pathogenicity and Th17-dependent autoimmunity.

Chao Wang, Allon Wagner, Johannes Fessler, David DeTomaso, Sarah Zaghouani, Yulin Zhou, Kerry Pierce, Raymond A Sobel, Clary Clish, Nir Yosef, Vijay K Kuchroo.

Glucose metabolism is a critical regulator of T cell function, largely thought to support their activation and effector differentiation. Here, we investigate the relevance of individual glycolytic reactions in determining the pathogenicity of T helper 17 (Th17) cells using single-cell RNA-seq and Compass, an algorithm we previously developed for estimating metabolic flux from single-cell transcriptomes. Surprisingly, Compass predicted that the metabolic shunt between 3-phosphoglycerate (3PG) and 2-phosphoglycerate (2PG) is inversely correlated with pathogenicity in these cells, whereas both its upstream and downstream reactions were positively correlated. Perturbation of phosphoglycerate mutase (PGAM), an enzyme required for 3PG to 2PG conversion, resulted in an increase in protein expression of IL2, IL17, and TNFa, as well as induction of a pathogenic gene expression program. Consistent with PGAM playing a pro-regulatory role, inhibiting PGAM in Th17 cells resulted in exacerbated autoimmune responses in the adoptive transfer model of experimental autoimmune encephalomyelitis (EAE). Finally, we further investigated the effects of modulating glucose concentration on Th17 cells in culture. Th17 cells differentiated under high- and low-glucose conditions substantially differed in their metabolic and effector transcriptomic programs, both central to Th17 function. Importantly, the PGAM-dependent gene module marks the least pathogenic state of Th17 cells irrespective of glucose concentration. Overall, our study identifies PGAM, contrary to other glycolytic enzymes, as a negative regulator of Th17 pathogenicity.

DOI: https://doi.org/10.1101/2024.08.18.607992
J Clin Invest. 2024 Sep 03. pii: e177606. [Epub ahead of print]134(17):

Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models.

Svena Verma, Sadna Budhu, Inna Serganova, Lauren Dong, Levi M Mangarin, Jonathan F Khan, Mamadou A Bah, Anais Assouvie, Yacine Marouf, Isabell Schulze, Roberta Zappasodi, Jedd D Wolchok, Taha Merghoub.

  Tumor reliance on glycolysis is a hallmark of cancer. Immunotherapy is more effective in controlling glycolysis-low tumors lacking lactate dehydrogenase (LDH) due to reduced tumor lactate efflux and enhanced glucose availability within the tumor microenvironment (TME). LDH inhibitors (LDHi) reduce glucose uptake and tumor growth in preclinical models, but their impact on tumor-infiltrating T cells is not fully elucidated. Tumor cells have higher basal LDH expression and glycolysis levels compared with infiltrating T cells, creating a therapeutic opportunity for tumor-specific targeting of glycolysis. We demonstrate that LDHi treatment (a) decreases tumor cell glucose uptake, expression of the glucose transporter GLUT1, and tumor cell proliferation while (b) increasing glucose uptake, GLUT1 expression, and proliferation of tumor-infiltrating T cells. Accordingly, increasing glucose availability in the microenvironment via LDH inhibition leads to improved tumor-killing T cell function and impaired Treg immunosuppressive activity in vitro. Moreover, combining LDH inhibition with immune checkpoint blockade therapy effectively controls murine melanoma and colon cancer progression by promoting effector T cell infiltration and activation while destabilizing Tregs. Our results establish LDH inhibition as an effective strategy for rebalancing glucose availability for T cells within the TME, which can enhance T cell function and antitumor immunity.

Keywords:  Cancer immunotherapy; Glucose metabolism; Immunology; Metabolism; Pharmacology

DOI:  https://doi.org/10.1172/JCI177606
Cell Rep. 2024 Aug 30. pii: S2211-1247(24)01041-6. [Epub ahead of print]43(9): 114690

The transcription regulator ID3 maintains tumor-specific memory CD8+ T cells in draining lymph nodes during tumorigenesis.

Ling Ran, Zhengliang Yue, Mengqu Ran, Qiao Liu, Xingxing Su, Lisha Wang, Shuqiong Wen, Luming Xu, Shun Lei, Zhanpeng Ou, Jianjun Hu, Yan Zhang, Chenxi Qin, Yuzhu Wang, Qinyi He, Yezi Chen, Wen Liu, Lilin Ye, Qizhao Huang, Lifan Xu.

  During tumorigenesis, the recently identified tumor-specific memory T cells in draining lymph nodes (TdLN-TTSM cells) play a pivotal role in tumor repression that gives rise to progenitor exhausted T (TPEX) cells and further replenishes tumor-specific CD8+ T cells residing in the tumor microenvironment (TME). However, how TTSM cells are maintained in TdLN is largely unknown. Here, we show that the transcription regulator ID3 (inhibitor of DNA binding 3) is highly expressed by TTSM cells compared with other CD8+ T cell subsets. The deficiency of ID3 significantly interrupts the maintenance of TTSM and TPEX cells, resulting in decreased tumor-infiltrating CD8+ T cells and impaired tumor control. Consistent with this, overexpression of ID3 in CD8+ T cells increases the TTSM cell population and enhances the anti-tumor immune response.

Keywords:  CP:; CP: Immunology; ID3; maintenance; tumor draining lymph node; tumor-specific memory T cell

DOI:  https://doi.org/10.1016/j.celrep.2024.114690
J Leukoc Biol. 2024 Aug 30. pii: qiae172. [Epub ahead of print]

IL-18 primes T cells with an antigen-inexperienced memory phenotype for proliferation and differentiation into effector cells through Notch signaling.

Wen Li, Denan Jin, Shinji Takai, Natsuko Inoue, Kyosuke Yamanishi, Yoshimasa Tanaka, Haruki Okamura.

  Recent studies have revealed that a subset of CD8+ T cells exhibit innate features and can be activated by cytokines. However, the precise mechanisms underlying the proliferation and differentiation of these cells remain unclear. Here, we demonstrated that CD44highCD8+ T cells in the mouse spleen express functional interleukin-18 (IL-18) receptors, whereas CD44lowCD8+ T cells do not. In response to IL-18 stimulation, these cells activated various metabolic pathways, upregulated the expression of surface molecules, such as c-Kit (CD117), CD25, and PD-1, and induced progression through the G1/S phase in the cell cycle. IL-18-primed cells, expressing a high-affinity receptor for IL-2, exhibited robust proliferation in response to IL-2 and underwent differentiation into effector cells. The splenic CD44highCD8+ T cells exhibited high expression levels of CD122, CD62L, CCR7, and CXCR3, along with CD5, indicating their potential for migration to the lymph nodes, where they could undergo expansion and terminal differentiation into effector cells. Additionally, in a tumor model, administration of IL-18 increased the accumulation of CD8+ T cells in both the lymph nodes and tumors. It is noteworthy that stimulation of CD44highCD8+ T cells with IL-18 upregulated the Notch-1 receptor and c-Myc. Moreover, inclusion of γ-secretase inhibitors attenuated the effect of IL-18 on both proliferation and interferon-γ production in the cells. These results demonstrate that IL-18 primes CD44highCD122highCXCR3highCD62LhighCD8+ T cells for expansion and differentiation into effector cells in a Notch signaling-dependent manner.

Keywords:  CD44highCD8+ T cells; G1/S phase; IL-18; Notch signaling; stem cell-like memory CD8+ T cells

DOI:  https://doi.org/10.1093/jleuko/qiae172
Acta Pharm Sin B. 2024 Aug;14(8): 3416-3431

Unlocking T cell exhaustion: Insights and implications for CAR-T cell therapy.

Dian Xiong, Haijun Yu, Zhi-Jun Sun.

  Chimeric antigen receptor T (CAR-T) cell therapy as a form of adoptive cell therapy (ACT) has shown significant promise in cancer treatment, demonstrated by the FDA-approved CAR-T cell therapies targeting CD19 or B cell maturation antigen (BCMA) for hematological malignancies, albeit with moderate outcomes in solid tumors. However, despite these advancements, the efficacy of CAR-T therapy is often compromised by T cell exhaustion, a phenomenon that impedes the persistence and effector function of CAR-T cells, leading to a relapse rate of up to 75% in patients treated with CD19 or CD22 CAR-T cells for hematological malignancies. Strategies to overcome CAR-T exhaustion employ state-of-the-art genomic engineering tools and single-cell sequencing technologies. In this review, we provide a comprehensive understanding of the latest mechanistic insights into T cell exhaustion and their implications for the current efforts to optimize CAR-T cell therapy. These insights, combined with lessons learned from benchmarking CAR-T based products in recent clinical trials, aim to address the challenges posed by T cell exhaustion, potentially setting the stage for the development of tailored next-generation approaches to cancer treatment.

Keywords:  CAR-T engineering; CAR-T therapy; Cancer immunotherapy; Combination therapy; Single-cell technologies; Spatial immune contexture; T cell exhaustion; Tumor immune microenvironment

DOI:  https://doi.org/10.1016/j.apsb.2024.04.022
Cancer Cell. 2024 Aug 26. pii: S1535-6108(24)00306-4. [Epub ahead of print]

Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8+ T cells.

Kevin Wang, Paulina Coutifaris, David Brocks, Guanning Wang, Tarek Azar, Sabrina Solis, Ajeya Nandi, Shaneaka Anderson, Nicholas Han, Sasikanth Manne, Evgeny Kiner, Chirag Sachar, Minke Lucas, Sangeeth George, Patrick K Yan, Melanie W Kier, Amy I Laughlin, Shawn Kothari, Josephine Giles, Divij Mathew, Reem Ghinnagow, Cecile Alanio, Ahron Flowers, Wei Xu, Daniel J Tenney, Xiaowei Xu, Ravi K Amaravadi, Giorgos C Karakousis, Lynn M Schuchter, Marcus Buggert, Derek Oldridge, Andy J Minn, Christian Blank, Jeffrey S Weber, Tara C Mitchell, Michael D Farwell, Ramin S Herati, Alexander C Huang.

  Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy. We develop the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points. Combination therapy results in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8+ T cells and exhausted CD8+ T cell (TEX) clones. Focused analyses of TEX identify that anti-CTLA-4 induces robust expansion and proliferation of progenitor TEX, which synergizes with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.

Keywords:  CTLA-4 blockade; Checkpoint blockade; PD-1 blockade; T cell exhaustion; clonotypic analysis; combination checkpoint blockade; immunotherapy; melanoma; progenitor exhausted CD8(+) T cells; single-cell sequencing

DOI:  https://doi.org/10.1016/j.ccell.2024.08.007
Aging Biol. 2023 ;pii: 20230014. [Epub ahead of print]1(1):

Cellular senescence exacerbates features of aging in the eyes.

Koji Kitazawa, Kohsaku Numa, Sandip Kumar Patel, Christina D King, Akifumi Matsumoto, Chie Sotozono, Pierre-Yves Desprez, Birgit Schilling, Judith Campisi.

  Aging is a process often associated with various age-related diseases. Senescence is one of the hallmarks of aging, and senescent cells acquire a complex, often pro-inflammatory, secretory phenotype termed the senescence-associated secretory phenotype (SASP). Here we show that ocular surface cells from human cornea become senescent upon X-irradiation, characterized by increased SA-β-gal activity, decreased cell proliferation, increased expression of p16, and disruption of epithelial barrier. Comprehensive transcriptomic and proteomic analysis revealed that human senescent ocular cells acquire a SASP that disrupts epithelial barrier function. During aging in mice, senescent ocular cells accumulate, resulting in decreased epithelial barrier and chronic inflammation. Lacrimal gland excision, which leads to symptoms of dry eye (DE), resulted in corneal opacity associated with severe angiogenesis only in aged mice but not in young mice, and early senolytic treatment protected old DE mice from corneal opacity. In conclusion, senescent cells alter the ocular microenvironment through their SASP and eliminating these cells could represent a potential approach to alleviate symptoms associated with aged ocular surface.

Keywords:  dry eye; lacrimal gland excision; mouse models; ocular surface; proteomics; senescence-associated secretory phenotype

DOI:  https://doi.org/10.59368/agingbio.20230014
Immunity. 2024 Aug 23. pii: S1074-7613(24)00407-2. [Epub ahead of print]

Inhibitory co-receptor Lag3 supports Foxp3+ regulatory T cell function by restraining Myc-dependent metabolic programming.

Dongkyun Kim, Giha Kim, Rongzhen Yu, Juyeun Lee, Sohee Kim, Mia R Gleason, Kevin Qiu, Elena Montauti, Li Lily Wang, Deyu Fang, Jaehyuk Choi, Navdeep S Chandel, Samuel Weinberg, Booki Min.

  Lymphocyte activation gene 3 (Lag3) is an inhibitory co-receptor expressed on activated T cells and has been proposed to regulate regulatory T (Treg) cell function. However, its precise modality and mechanisms remain elusive. We generated Treg cell-specific Lag3-mutant mouse models and found that Lag3 was essential for Treg cell control of autoimmunity. RNA sequencing analysis revealed that Lag3 mutation altered genes associated with metabolic processes, especially Myc target genes. Myc expression in Lag3-mutant Treg cells was increased to the level seen in conventional T helper (Th)1-type effector cells and directly correlated with their metabolic profiles and in vivo suppressive functions. The phosphatidylinositol 3-kinase (PI3K)-Akt-Rictor pathway was activated in Lag3-mutant Treg cells, and inhibiting PI3K, Rictor, or lactate dehydrogenase A (Ldha), a key Myc target enzyme converting pyruvate to lactate, was sufficient to restore normal metabolism and suppressive function in Lag3-mutant Treg cells. These findings indicate that Lag3 supports Treg cell suppression partly by tuning Myc-dependent metabolic programming.

Keywords:  Lag3; Myc; Treg cells; autoimmunity; metabolism

DOI:  https://doi.org/10.1016/j.immuni.2024.08.008
bioRxiv. 2024 Aug 25. pii: 2024.08.24.609521. [Epub ahead of print]

A Unified Atlas of T cell Glycophysiology.

Fauzia N Izzati, Hani Choksi, Paolo Giuliana, Diala Abd-Rabbo, Heidi Elsaesser, Aled Blundell, Vanessa Affe, Vinicius Kannen, Zeinab Jame-Chenarboo, Edward Schmidt, Meggie Kuypers, David B Avila, Eric S Y Chiu, Dzhangar Badmaev, Haissi Cui, Jason Matthews, Thierry Mallevaey, Matthew S Macauley, David G Brooks, Landon J Edgar.

Glycans are emerging as important regulators of T cell function but remain poorly characterized across the functionally distinct populations that exist in vivo . Here, we couple single-cell analysis technologies with soluble lectins and chemical probes to interrogate glycosylation patterns on major T cell populations across multiple mouse and human tissues. Our analysis focused on terminal glycan epitopes with immunomodulatory functions, including sialoglycan ligands for Siglecs. We demonstrate that glycosylation patterns are diverse across the resting murine T cell repertoire and dynamically remodelled in response to antigen-specific stimulation. Surprisingly, we find that human T cell populations do not share the same glycoprofiles or glycan remodelling dynamics as their murine counterparts. We show that these differences can be explained by divergent regulation of glycan biosynthesis pathways between the species. These results highlight fundamental glycophysiological differences between mouse and human T cells and reveal features that are critical to consider for glycan-targeted therapies.

DOI: https://doi.org/10.1101/2024.08.24.609521
bioRxiv. 2024 Jul 23. pii: 2024.07.22.604599. [Epub ahead of print]

Dietary iron deficiency impairs effector function of memory T cells following influenza infection.

Marissa C Bradley, Joshua Gray, Francesca La Carpia, Emma Idzikowski, Rebecca Guyer, Kalpana Pethe, Eldad A Hod, Thomas J Connors.

The establishment of memory T cell responses is critical to protection against pathogens and is influenced by the conditions under which memory formation occurs. Iron is an essential micronutrient for multiple immunologic processes and nutritional deficiency is a common problem worldwide. Despite its prevalence, the impact of nutritional iron deficiency on the establishment of memory T cell responses is not fully understood. In this study we investigate the impact of nutritional iron deficiency on the generation, phenotype, and function of memory T cell responses using a murine model of dietary iron modulation in the context of influenza infection. Iron deficient mice have decreased systemic iron levels and develop significant anemia. Increased T cell expression of the transferrin receptor (CD71) is seen in iron deficient mice at baseline. During primary influenza infection, iron deficient mice experience increased weight loss and phenotypic evidence of impairments in T cell activation. Following recovery from infection, iron deficient mice generate increased influenza specific memory T cells which exhibit impaired ability to produce IFNγ, most notably within the lung. Importantly, the ability to produce IFNγ and TNFα is not recovered by co-culture with iron replete dendritic cells, suggesting a T cell intrinsic alteration in functional memory formation. Altogether, these results isolate a critical effect of nutritional iron deficiency on T cell memory development and function.

DOI: https://doi.org/10.1101/2024.07.22.604599
Nat Aging. 2024 Sep 04.

Spermidine controls autophagy during fasting.

Anna Kriebs.

DOI: https://doi.org/10.1038/s43587-024-00710-3
Sci China Life Sci. 2024 Sep 02.

An in-depth understanding of the role and mechanisms of T cells in immune organ aging and age-related diseases.

Yudai Xu, Zijian Wang, Shumin Li, Jun Su, Lijuan Gao, Junwen Ou, Zhanyi Lin, Oscar Junhong Luo, Chanchan Xiao, Guobing Chen.

  T cells play a critical and irreplaceable role in maintaining overall health. However, their functions undergo alterations as individuals age. It is of utmost importance to comprehend the specific characteristics of T-cell aging, as this knowledge is crucial for gaining deeper insights into the pathogenesis of aging-related diseases and developing effective therapeutic strategies. In this review, we have thoroughly examined the existing studies on the characteristics of immune organ aging. Furthermore, we elucidated the changes and potential mechanisms that occur in T cells during the aging process. Additionally, we have discussed the latest research advancements pertaining to T-cell aging-related diseases. These findings provide a fresh perspective for the study of T cells in the context of aging.

Keywords:  T cell; age-related diseases; aging; immune organ

DOI:  https://doi.org/10.1007/s11427-024-2695-x