bims-imseme 2023-11-19 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2023–11–19
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Single-cell CRISPR screens in vivo map T cell fate regulomes in cancer.
One-carbon unit supplementation fuels tumor-infiltrating T cells and augments checkpoint blockade.
Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8+ T cells via ME1 up-regulation.
Emergence and fate of stem cell-like Tcf7+ CD8+ T cells during a primary immune response to viral infection.
The Role of CD4 T Cell Help in CD8 T Cell Differentiation and Function During Chronic Infection and Cancer.
Excessive apoptosis of Rip1-deficient T cells leads to premature aging.
Reliable Hallmarks and Biomarkers of Senescent Lymphocytes.
Rapid activation of IL-2 receptor signaling by CD301b + DC-derived IL-2 dictates the outcome of helper T cell differentiation.
Comprehensive single cell aging atlas of mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer.
Prostate cancer cell-derived exosomal IL-8 fosters immune evasion by disturbing glucolipid metabolism of CD8+ T cell.
Splenocytes with fucosylation deficiency promote T cell proliferation and differentiation through thrombospondin-1 downregulation.
Single-cell atlas of healthy human blood unveils age-related loss of NKG2C+GZMB-CD8+ memory T cells and accumulation of type 2 memory T cells.
Bibliometric and visual analyses of trends in the field of T cell exhaustion research: Findings from 2000 to 2022.

Nature. 2023 Nov 15.

Single-cell CRISPR screens in vivo map T cell fate regulomes in cancer.

Peipei Zhou, Hao Shi, Hongling Huang, Xiang Sun, Sujing Yuan, Nicole M Chapman, Jon P Connelly, Seon Ah Lim, Jordy Saravia, Anil Kc, Shondra M Pruett-Miller, Hongbo Chi.

CD8+ cytotoxic T cells (CTLs) orchestrate antitumour immunity and exhibit inherent heterogeneity1,2, with precursor exhausted T (Tpex) cells but not terminally exhausted T (Tex) cells capable of responding to existing immunotherapies3-7. The gene regulatory network that underlies CTL differentiation and whether Tex cell responses can be functionally reinvigorated are incompletely understood. Here we systematically mapped causal gene regulatory networks using single-cell CRISPR screens in vivo and discovered checkpoints for CTL differentiation. First, the exit from quiescence of Tpex cells initiated successive differentiation into intermediate Tex cells. This process is differentially regulated by IKAROS and ETS1, the deficiencies of which dampened and increased mTORC1-associated metabolic activities, respectively. IKAROS-deficient cells accumulated as a metabolically quiescent Tpex cell population with limited differentiation potential following immune checkpoint blockade (ICB). Conversely, targeting ETS1 improved antitumour immunity and ICB efficacy by boosting differentiation of Tpex to intermediate Tex cells and metabolic rewiring. Mechanistically, TCF-1 and BATF are the targets for IKAROS and ETS1, respectively. Second, the RBPJ-IRF1 axis promoted differentiation of intermediate Tex to terminal Tex cells. Accordingly, targeting RBPJ enhanced functional and epigenetic reprogramming of Tex cells towards the proliferative state and improved therapeutic effects and ICB efficacy. Collectively, our study reveals that promoting the exit from quiescence of Tpex cells and enriching the proliferative Tex cell state act as key modalities for antitumour effects and provides a systemic framework to integrate cell fate regulomes and reprogrammable functional determinants for cancer immunity.

DOI: https://doi.org/10.1038/s41586-023-06733-x
bioRxiv. 2023 Nov 03. pii: 2023.11.01.565193. [Epub ahead of print]

One-carbon unit supplementation fuels tumor-infiltrating T cells and augments checkpoint blockade.

Xincheng Xu, Zihong Chen, Caroline R Bartman, Xi Xing, Kellen Olszewski, Joshua D Rabinowitz.

Nucleotides perform important metabolic functions, carrying energy and feeding nucleic acid synthesis. Here, we use isotope tracing-mass spectrometry to quantitate the contributions to purine nucleotides of salvage versus de novo synthesis. We further explore the impact of augmenting a key precursor for purine synthesis, one-carbon (1C) units. We show that tumors and tumor-infiltrating T cells (relative to splenic T cells) synthesize purines de novo . Purine synthesis requires two 1C units, which come from serine catabolism and circulating formate. Shortage of 1C units is a potential bottleneck for anti-tumor immunity. Elevating circulating formate drives its usage by tumor-infiltrating T cells. Orally administered methanol functions as a formate pro-drug, with deuteration enabling control of formate-production kinetics. In MC38 tumors, safe doses of methanol raise formate levels and augment anti-PD-1 checkpoint blockade, tripling durable regressions. Thus, 1C deficiency can gate antitumor immunity and this metabolic checkpoint can be overcome with pharmacological 1C supplementation.
Statement of significance: Checkpoint blockade has revolutionized cancer therapy. Durable tumor control, however, is achieved in only a minority of patients. We show that the efficacy of anti-PD-1 blockade can be enhanced by metabolic supplementation with one-carbon donors. Such donors support nucleotide synthesis in tumor-infiltrating T cells and merit future clinical evaluation.

DOI: https://doi.org/10.1101/2023.11.01.565193
Sci Adv. 2023 Nov 17. 9(46): eadi2414

Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8+ T cells via ME1 up-regulation.

Joanina K Gicobi, Zhiming Mao, Grace DeFranco, Jacob B Hirdler, Ying Li, Vianca V Vianzon, Emilia R Dellacecca, Michelle A Hsu, Whitney Barham, Yiyi Yan, Aaron S Mansfield, Yi Lin, Xiaosheng Wu, Taro Hitosugi, Dawn Owen, Michael P Grams, Jacob J Orme, Fabrice Lucien, Hu Zeng, Sean S Park, Haidong Dong.

Patients with advanced cancers who either do not experience initial response to or progress while on immune checkpoint inhibitors (ICIs) receive salvage radiotherapy to reduce tumor burden and tumor-related symptoms. Occasionally, some patients experience substantial global tumor regression with a rebound of cytotoxic CD8+ T cells. We have termed the rebound of cytotoxic CD8+ T cells in response to salvage therapy as T cell resilience and examined the underlying mechanisms of resilience. Resilient T cells are enriched for CX3CR1+ CD8+ T cells with low mitochondrial membrane potential, accumulate less reactive oxygen species (ROS), and express more malic enzyme 1 (ME1). ME1 overexpression enhanced the cytotoxicity and expansion of effector CD8+ T cells partially via the type I interferon pathway. ME1 also increased mitochondrial respiration while maintaining the redox state balance. ME1 increased the cytotoxicity of peripheral lymphocytes from patients with advanced cancers. Thus, preserved resilient T cells in patients rebound after salvage therapy and ME1 enhances their resiliency.

DOI: https://doi.org/10.1126/sciadv.adi2414
Sci Immunol. 2023 Nov 17. 8(89): eadh3113

Emergence and fate of stem cell-like Tcf7+ CD8+ T cells during a primary immune response to viral infection.

Joana Gomes Silva, Daniela Pais Ferreira, Alexandre Dumez, Tania Wyss, Romain Veber, Maxime Danilo, Daniel D Pinschewer, Mélanie Charmoy, Werner Held.

In response to infection, naïve CD8+ T (TN) cells yield a large pool of short-lived terminal effector (TTE) cells that eliminate infected host cells. In parallel, a minor population of stem cell-like central memory (TCM) cells forms, which has the capacity to maintain immunity after pathogen clearance. It has remained uncertain whether stem-like TCM cells arise by dedifferentiation from a subset of cytolytic TTE cells or whether priming generates stem-like cells capable of seeding the TCM compartment and, if so, when cytolytic TTE cells branch off. Here, we show that CD8+ T cells with stem-like properties, which are identified by the expression of TCF1 (encoded by Tcf7), are present across the primary response to infection. Priming programs TN cells to undergo multiple cell divisions, over the course of which TCF1 expression is maintained. These TCF1+ cells further expand relatively independently of systemic inflammation, antigen dose, or affinity, and they quantitatively yield TCF1+ TCM cells after pathogen clearance. Inflammatory signals suppress TCF1 expression in early divided TCF1+ cells. TCF1 down-regulation is associated with the irreversible loss of self-renewal capacity and the silencing of stem/memory genes, which precedes the stable acquisition of a TTE state. TCF1 expression restrains cell cycling, explaining in part the limited expansion of TCF1+ relative to TCF1- cells during the primary response. Thus, our data are consistent with terminal differentiation of effector cells being a step-wise process that is initiated by inflammation in primed stem-like cells, which would otherwise become central memory cells by default.

DOI: https://doi.org/10.1126/sciimmunol.adh3113
Immune Netw. 2023 Oct;23(5): e41

The Role of CD4 T Cell Help in CD8 T Cell Differentiation and Function During Chronic Infection and Cancer.

Paytsar Topchyan, Siying Lin, Weiguo Cui.

  CD4 and CD8 T cells are key players in the immune response against both pathogenic infections and cancer. CD4 T cells provide help to CD8 T cells via multiple mechanisms, including licensing dendritic cells (DCs), co-stimulation, and cytokine production. During acute infection and vaccination, CD4 T cell help is important for the development of CD8 T cell memory. However, during chronic viral infection and cancer, CD4 helper T cells are critical for the sustained effector CD8 T cell response, through a variety of mechanisms. In this review, we focus on T cell responses in conditions of chronic Ag stimulation, such as chronic viral infection and cancer. In particular, we address the significant role of CD4 T cell help in promoting effector CD8 T cell responses, emerging techniques that can be utilized to further our understanding of how these interactions may take place in the context of tertiary lymphoid structures, and how this key information can be harnessed for therapeutic utility against cancer.

Keywords:  CD4 T cells; CD8 T cells; Cancer; Chronic infection; Immunotherapy

DOI:  https://doi.org/10.4110/in.2023.23.e41
EMBO Rep. 2023 Nov 15. e57925

Excessive apoptosis of Rip1-deficient T cells leads to premature aging.

Lingxia Wang, Xixi Zhang, Haiwei Zhang, Kaili Lu, Ming Li, Xiaoming Li, Yangjing Ou, Xiaoming Zhao, Xiaoxia Wu, Xuanhui Wu, Jianling Liu, Mingyan Xing, Han Liu, Yue Zhang, Yongchang Tan, Fang Li, Xiaoxue Deng, Jiangshan Deng, Xiaojie Zhang, Jinbao Li, Yuwu Zhao, Qiurong Ding, Haikun Wang, Xiuzhe Wang, Yan Luo, Ben Zhou, Haibing Zhang.

  In mammals, the most remarkable T cell variations with aging are the shrinking of the naïve T cell pool and the enlargement of the memory T cell pool, which are partially caused by thymic involution. However, the mechanism underlying the relationship between T-cell changes and aging remains unclear. In this study, we find that T-cell-specific Rip1 KO mice show similar age-related T cell changes and exhibit signs of accelerated aging-like phenotypes, including inflammation, multiple age-related diseases, and a shorter lifespan. Mechanistically, Rip1-deficient T cells undergo excessive apoptosis and promote chronic inflammation. Consistent with this, blocking apoptosis by co-deletion of Fadd in Rip1-deficient T cells significantly rescues lymphopenia, the imbalance between naïve and memory T cells, and aging-like phenotypes, and prolongs life span in T-cell-specific Rip1 KO mice. These results suggest that the reduction and hyperactivation of T cells can have a significant impact on organismal health and lifespan, underscoring the importance of maintaining T cell homeostasis for healthy aging and prevention or treatment of age-related diseases.

Keywords:  RIP1; apoptosis; inflammation; premature aging

DOI:  https://doi.org/10.15252/embr.202357925
Int J Mol Sci. 2023 Oct 27. pii: 15653. [Epub ahead of print]24(21):

Reliable Hallmarks and Biomarkers of Senescent Lymphocytes.

Yuliya S Martyshkina, Valeriy P Tereshchenko, Daria A Bogdanova, Stanislav A Rybtsov.

  The phenomenon of accumulation of senescent adaptive immunity cells in the elderly is attracting attention due to the increasing risk of global epidemics and aging of the global population. Elderly people are predisposed to various infectious and age-related diseases and are at higher risk of vaccination failure. The accumulation of senescent cells increases age-related background inflammation, "Inflammaging", causing lymphocyte exhaustion and cardiovascular, neurodegenerative, autoimmune and cancer diseases. Here, we present a comprehensive contemporary review of the mechanisms and phenotype of senescence in the adaptive immune system. Although modern research has not yet identified specific markers of aging lymphocytes, several sets of markers facilitate the separation of the aging population based on normal memory and exhausted cells for further genetic and functional analysis. The reasons for the higher predisposition of CD8+ T-lymphocytes to senescence compared to the CD4+ population are also discussed. We point out approaches for senescent-lymphocyte-targeting markers using small molecules (senolytics), antibodies and immunization against senescent cells. The suppression of immune senescence is the most relevant area of research aimed at developing anti-aging and anti-cancer therapy for prolonging the lifespan of the global population.

Keywords:  biomarkers of senescence; immunosenescence; senescent lymphocytes

DOI:  https://doi.org/10.3390/ijms242115653
bioRxiv. 2023 Oct 31. pii: 2023.10.26.564276. [Epub ahead of print]

Rapid activation of IL-2 receptor signaling by CD301b + DC-derived IL-2 dictates the outcome of helper T cell differentiation.

Naoya Tatsumi, Jihad El-Fenej, Alejandro Davila-Pagan, Yosuke Kumamoto.

Effector T helper (Th) cell differentiation is fundamental to functional adaptive immunity. Different subsets of dendritic cells (DCs) preferentially induce different types of Th cells, but the fate instruction mechanism for Th type 2 (Th2) differentiation remains enigmatic, as the critical DC-derived cue has not been clearly identified. Here, we show that CD301b + DCs, a major Th2-inducing DC subset, drive Th2 differentiation through cognate interaction by 'kick-starting' IL-2 receptor signaling in CD4T cells. Mechanistically, CD40 engagement induces IL-2 production selectively from CD301b + DCs to maximize CD25 expression in CD4 T cells, which is required specifically for the Th2 fate decision. On the other hand, CD25 in CD301b + DCs facilitates directed action of IL-2 toward cognate CD4T cells. Furthermore, CD301b + DC-derived IL-2 skews CD4T cells away from the T follicular helper fate. These results highlight the critical role of DC-intrinsic CD40-IL-2 axis in bifurcation of Th cell fate.

DOI: https://doi.org/10.1101/2023.10.26.564276
bioRxiv. 2023 Oct 23. pii: 2023.10.20.563147. [Epub ahead of print]

Comprehensive single cell aging atlas of mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer.

Brittany L Angarola, Siddhartha Sharma, Neerja Katiyar, Hyeon Gu Kang, Djamel Nehar-Belaid, SungHee Park, Rachel Gott, Giray N Eryilmaz, Mark A LaBarge, Karolina Palucka, Jeffrey H Chuang, Ron Korstanje, Duygu Ucar, Olga Anczukow.

Aging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. We investigate how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single cell resolution, yielding a comprehensive resource for aging and cancer biology. Aged epithelial cells exhibit epigenetic and transcriptional changes in metabolic, pro-inflammatory, or cancer-associated genes. Aged stromal cells downregulate fibroblast marker genes and upregulate markers of senescence and cancer-associated fibroblasts. Among immune cells, distinct T cell subsets ( Gzmk + , memory CD4 + , γδ) and M2-like macrophages expand with age. Spatial transcriptomics reveal co-localization of aged immune and epithelial cells in situ . Lastly, transcriptional signatures of aging mammary cells are found in human breast tumors, suggesting mechanistic links between aging and cancer. Together, these data uncover that epithelial, immune, and stromal cells shift in proportions and cell identity, potentially impacting cell plasticity, aged microenvironment, and neoplasia risk.

DOI: https://doi.org/10.1101/2023.10.20.563147
Cell Rep. 2023 Nov 13. pii: S2211-1247(23)01436-5. [Epub ahead of print]42(11): 113424

Prostate cancer cell-derived exosomal IL-8 fosters immune evasion by disturbing glucolipid metabolism of CD8+ T cell.

Fan Xu, Xiumei Wang, Ying Huang, Xiaoqian Zhang, Wenbo Sun, Yuanyuan Du, Zhi Xu, Hengyuan Kou, Shuyi Zhu, Caidong Liu, Xiaowei Wei, Xiao Li, Qin Jiang, Yong Xu.

  Depletion of CD8+ T cells is a major obstacle in immunotherapy; however, the relevant mechanisms remain largely unknown. Here, we showed that prostate cancer (PCa) cell-derived exosomes hamper CD8+ T cell function by transporting interleukin-8 (IL-8). Compared to the low IL-8 levels detected in immune cells, PCa cells secreted the abundance of IL-8 and further accumulated in exosomes. The delivery of PCa cell-derived exosomes into CD8+ T cells exhausted the cells through enhanced starvation. Mechanistically, exosomal IL-8 overactivated PPARα in recipient cells, thereby decreasing glucose utilization by downregulating GLUT1 and HK2 but increasing fatty acid catabolism via upregulation of CPT1A and ACOX1. PPARα further activates uncoupling protein 1 (UCP1), leading to fatty acid catabolism for thermogenesis rather than ATP synthesis. Consequently, inhibition of PPARα and UCP1 restores CD8+ T cell proliferation by counteracting the effect of exosomal IL-8. This study revealed that the tumor exosome-activated IL-8-PPARα-UCP1 axis harms tumor-infiltrating CD8+ T cells by interfering with energy metabolism.

Keywords:  CD8(+) T cell; CP: Cancer; CP: Immunology; PPARα; exosome; glucolipid metabolism; interleukin-8; prostate cancer

DOI:  https://doi.org/10.1016/j.celrep.2023.113424
Immunology. 2023 Nov 13.

Splenocytes with fucosylation deficiency promote T cell proliferation and differentiation through thrombospondin-1 downregulation.

Jung Hwa Ko, Jin Suk Ryu, Jang-Hee Oh, Joo Youn Oh.

  Fucosylation plays a critical role in cell-to-cell interactions and disease progression. However, the effects of fucosylation on splenocytes and their interactions with T cells remain unclear. In this study, we aimed to explore the transcriptome profiles of splenocytes deficient in fucosyltransferase (FUT) 1, an enzyme that mediates fucosylation, and investigate their impact on the proliferation and differentiation of T cells. We analysed and compared the transcriptomes of splenocytes isolated from Fut1 knockout (KO) mice and those from wild-type (WT) mice using RNA-seq. Additionally, we examined the effects of Fut1 KO splenocytes on CD4 T cell proliferation and differentiation, in comparison to WT splenocytes, and elucidated the mechanisms involved. The comparative analysis of transcriptomes between Fut1 KO and WT splenocytes revealed that thrombospondin-1, among the genes related to immune response and inflammation, was the most highly downregulated gene in Fut1 KO splenocytes. The reduced expression of thrombospondin-1 was further confirmed using qRT-PCR and flow cytometry. In coculture experiments, Fut1 KO splenocytes promoted the proliferation of CD4 T cells and drove their differentiation toward Th1 and Th17 cells, compared with WT splenocytes. Moreover, the levels of IL-2, IFN-γ and IL-17 were increased, while IL-10 was decreased, in T cells cocultured with Fut1 KO splenocytes compared with those with WT splenocytes. These effects of Fut1 KO splenocytes on T cells were reversed when thrombospondin-1 was replenished. Taken together, our results demonstrate that splenocytes with Fut1 deficiency promote CD4 T cell proliferation and Th1/Th17 differentiation at least in part through thrombospondin-1 downregulation.

Keywords:  T cell; fucosylation; fucosyltransferase 1; splenocyte; thrombospondin-1

DOI:  https://doi.org/10.1111/imm.13716
Immunity. 2023 Nov 05. pii: S1074-7613(23)00453-3. [Epub ahead of print]

Single-cell atlas of healthy human blood unveils age-related loss of NKG2C+GZMB-CD8+ memory T cells and accumulation of type 2 memory T cells.

Marina Terekhova, Amanda Swain, Pavla Bohacova, Ekaterina Aladyeva, Laura Arthur, Anwesha Laha, Denis A Mogilenko, Samantha Burdess, Vladimir Sukhov, Denis Kleverov, Barbora Echalar, Petr Tsurinov, Roman Chernyatchik, Kamila Husarcikova, Maxim N Artyomov.

  Extensive, large-scale single-cell profiling of healthy human blood at different ages is one of the critical pending tasks required to establish a framework for the systematic understanding of human aging. Here, using single-cell RNA/T cell receptor (TCR)/BCR-seq with protein feature barcoding, we profiled 317 samples from 166 healthy individuals aged 25-85 years old. From this, we generated a dataset from ∼2 million cells that described 55 subpopulations of blood immune cells. Twelve subpopulations changed with age, including the accumulation of GZMK+CD8+ T cells and HLA-DR+CD4+ T cells. In contrast to other T cell memory subsets, transcriptionally distinct NKG2C+GZMB-CD8+ T cells counterintuitively decreased with age. Furthermore, we found a concerted age-associated increase in type 2/interleukin (IL)4-expressing memory subpopulations across CD4+ and CD8+ T cell compartments (CCR4+CD8+ Tcm and Th2 CD4+ Tmem), suggesting a systematic functional shift in immune homeostasis with age. Our work provides novel insights into healthy human aging and a comprehensive annotated resource.

Keywords:  CCR4(+)CD8(+) T cells; NKG2C(+)GZMB(-)CD8(+) T cells; PBMC; TCR/BCR sequencing; Th2; aging; human; scRNA-seq; surface protein

DOI:  https://doi.org/10.1016/j.immuni.2023.10.013
Int J Immunopathol Pharmacol. 2023 Jan-Dec;37:37 3946320231215219

Bibliometric and visual analyses of trends in the field of T cell exhaustion research: Findings from 2000 to 2022.

Ziling Liu, Huan Wan, Yao Tan, Deshuang Li, Jianguo Huang, Chuanhe Zhang, Fangyuan Liu, Bo Qin.

   BACKGROUND: T cell exhaustion refers to a state wherein T cells become less functional as a result of their prolonged exposure to cognate antigens. A wealth of T cell exhaustion-focused research has been conducted in recent decades, transforming the current understanding of this biologically relevant process. However, there have not been any comprehensive bibliometric analyses to date focused on clarifying the T cell exhaustion-related research landscape. Here, a bibliometric analysis was thus conducted with the goal of better elucidating the current state of knowledge and emerging research hotspots in this field.
METHODS: The Web of Science Core Collection was searched for articles and reviews related to T cell exhaustion, with the CiteSpace and VOSviewer programs then being employed to analyze the countries, institutions, authors, references, and keywords associated with studies in this research space.
RESULTS: In total, 2676 studies were incorporated in this analysis, highlighting progressive annual increases in the number of T cell exhaustion-focused publications over the study period. These publications were affiliated with 3117 institutions in 85 countries, with the USA and China being the largest contributors to the field. Of the 18,032 authors associated with these publications, E. John Wherry exhibited the highest publication count and the greatest citation frequency. Keyword analyses indicated that immunotherapy, T cell exhaustion, and PD-1 are the dominant foci for T cell exhaustion-related research.
CONCLUSION: These findings highlight the importance of collaborations among institutions and nations in order to further propel novel studies of T cell exhaustion. Efforts to unravel the signal transduction and transcriptional mechanisms underlying the onset of T cell exhaustion were also identified as an emerging hotspot in this field. Ultimately, these results support the pivotal status of T cell exhaustion research as a key direction for immunotherapeutic research and development efforts in the coming years.

Keywords:  T cells; bibliometrics; exhaustion; immunotherapy

DOI:  https://doi.org/10.1177/03946320231215219