bims-imseme 2024-02-11 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2024‒02‒11
fourteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Mitochondrial Transplantation promotes protective effector and memory CD4 + T cell response during Mycobacterium tuberculosis infection and diminishes exhaustion and senescence in elderly CD4 + T cells.
PREX1 improves homeostatic proliferation to maintain a naïve CD4 T cell compartment in older age.
1-Pyrroline-5-carboxylate inhibit T cell glycolysis in prostate cancer microenvironment by SHP1/PKM2/LDHB axis.
Per-cell histone acetylation is associated with terminal differentiation in human T cells.
The interplay between obesity, immunosenescence, and insulin resistance.
Functional impairment of "helpless" CD8 + memory T cells is transient and driven by prolonged but finite cognate antigen presentation.
Nanoparticle-Based Immunotherapy for Reversing T-Cell Exhaustion.
EP300 restores the glycolytic activity and anti-tumor function of CD8+ cytotoxic T cells in nasopharyngeal carcinoma.
ECSIT facilitates memory CD8+ T cell development by mediating fumarate synthesis during viral infection and tumorigenesis.
Lactic acid induces transcriptional repression of macrophage inflammatory response via histone acetylation.
Single cell analysis revealed that two distinct, unique CD4+ T cell subsets were increased in the small intestinal intraepithelial lymphocytes of aged mice.
Rab37 mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion in lung cancer.
Exhausted tumor-infiltrating CD39+CD103+ CD8+ T cells unveil potential for increased survival in human pancreatic cancer.
Antigen-specific age-related memory CD8 T cells induce and track Alzheimer's-like neurodegeneration.

bioRxiv. 2024 Jan 27. pii: 2024.01.24.577036. [Epub ahead of print]

Mitochondrial Transplantation promotes protective effector and memory CD4 + T cell response during Mycobacterium tuberculosis infection and diminishes exhaustion and senescence in elderly CD4 + T cells.

Colwyn A Headley, Shalini Gautam, Angelica Olmo-Fontanez, Andreu Garcia-Vilanova, Varun Dwivedi, Alyssa Schami, Susan Weintraub, Philip S Tsao, Jordi B Torrelles, Joanne Turner.

Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis ( M.tb ), remains a significant health concern worldwide, especially in populations with weakened or compromised immune systems, such as the elderly. Proper adaptive immune function, particularly a CD4 + T cell response, is central to host immunity against M.tb . Chronic infections, such as M.tb , as well as aging promote T cell exhaustion and senescence, which can impair immune control and promote progression to TB disease. Mitochondrial dysfunction contributes to T cell dysfunction, both in aging and chronic infections and diseases. Mitochondrial perturbations can disrupt cellular metabolism, enhance oxidative stress, and impair T-cell signaling and effector functions. This study examined the impact of mitochondrial transplantation (mito-transfer) on CD4 + T cell differentiation and function using aged mouse models and human CD4 + T cells from elderly individuals. Our study revealed that mito-transfer in naïve CD4 + T cells promoted the generation of protective effector and memory CD4 + T cells during M.tb infection in mice. Further, mito-transfer enhanced the function of elderly human T cells by increasing their mitochondrial mass and modulating cytokine production, which in turn reduced exhaustion and senescence cell markers. Our results suggest that mito-transfer could be a novel strategy to reestablish aged CD4 + T cell function, potentially improving immune responses in the elderly and chronic TB patients, with a broader implication for other diseases where mitochondrial dysfunction is linked to T cell exhaustion and senescence.

DOI: https://doi.org/10.1101/2024.01.24.577036
JCI Insight. 2024 Feb 08. pii: e172848. [Epub ahead of print]

PREX1 improves homeostatic proliferation to maintain a naïve CD4 T cell compartment in older age.

Huimin Zhang, Hirohisa Okuyama, Abhinav Jain, Rohit R Jadhav, Bowen Wu, Ines Sturmlechner, Jose Morales, Shozo Ohtsuki, Cornelia M Weyand, Jörg J Goronzy.

  The human adult immune system maintains normal T-cell counts and compensates for T-cell loss over lifetime mainly through peripheral homeostatic proliferation after the ability of the thymus to generate new T cells has rapidly declined at adolescence. This process is mainly driven by STAT5-activating cytokines, most importantly IL-7, and is very effective in maintaining a large naïve CD4 T cell compartment into older age. Here, we describe that naïve CD4 T cells undergo adaptations to optimize IL-7 responses by upregulating the guanine-nucleotide exchange factor PREX1 at older age. PREX1 promotes nuclear translocation of phosphorylated STAT5, thereby supporting homeostatic proliferation in response to IL-7. Through the same mechanism, increased expression of PREX1 also biases naïve cells to differentiate into effector T cells. These findings are consistent with the concept that primarily beneficial adaptations during aging, i.e., improved homeostasis, account for unfavorable functions of the aged immune system, in this case biased differentiation.

Keywords:  Adaptive immunity; Aging; Immunology; T cells

DOI:  https://doi.org/10.1172/jci.insight.172848
Cell Commun Signal. 2024 Feb 08. 22(1): 101

1-Pyrroline-5-carboxylate inhibit T cell glycolysis in prostate cancer microenvironment by SHP1/PKM2/LDHB axis.

Lei Chang, Guohao Li, Shan Jiang, Jie Li, Jin Yang, Kavita Shah, Le Zhou, Hanrui Song, Leyuan Deng, Zhiguo Luo, Yonglian Guo, Yutao Yan.

  BACKGROUND: Our previous studies demonstrated that 1-Pyrroline-5-carboxylate (P5C) released by prostate cancer cells inhibits T cell proliferation and function by increasing SHP1 expression. We designed this study to further explore the influence of P5C on T cell metabolism, and produced an antibody for targeting P5C to restore the functions of T cells.METHOD: We co-immunoprecipated SHP1 from T cells and analyzed the proteins that were bound to it using liquid chromatography mass spectrometry (LC/MS-MS). The influence of P5C on T cells metabolism was also detected by LC/MS-MS. Seahorse XF96 analyzer was further used to identify the effect of P5C on T cells glycolysis. We subsequently designed and produced an antibody for targeting P5C by monoclonal technique and verified its effectiveness to restore the function of T cells in vitro and in vivo.
RESULT: PKM2 and LDHB bind SHP1 in T cells, and P5C could increase the levels of p-PKM2 while having no effect on the levels of PKM2 and LDHB. We further found that P5C influences T cell energy metabolism and carbohydrate metabolism. P5C also inhibits the activity of PKM2 and decreases the content of intracellular lactic acid while increasing the activity of LDH. Using seahorse XF96 analyzer, we confirmed that P5C remarkably inhibits glycolysis in T cells. We produced an antibody for targeting P5C by monoclonal technique and verified that the antibody could oppose the influence of P5C to restore the process of glycolysis and function in T cells. Meanwhile, the antibody also inhibits the growth of prostate tumors in an animal model.
CONCLUSION: Our study revealed that P5C inhibits the process of glycolysis in T cells by targeting SHP1/PKM2/LDHB complexes. Moreover, it is important that the antibody for targeting P5C could restore the function of T cells and inhibit the growth of prostate tumors.

Keywords:  Glycolysis; P5C; Prostate cancer; SHP1; T cell

DOI:  https://doi.org/10.1186/s12964-024-01493-1
Clin Epigenetics. 2024 Feb 06. 16(1): 21

Per-cell histone acetylation is associated with terminal differentiation in human T cells.

Cheng Yang, You Li, Yaqiu Hu, Qian Li, Yinghua Lan, Yongguo Li.

  BACKGROUND: Epigenetic remodeling at effector gene loci has been reported to be critical in regulating T cell differentiation and function. However, efforts to investigate underlying epigenetic mechanisms that control T cell behaviors have been largely hindered by very limited experimental tools, especially in humans.RESULTS: In this study, we employed a flow cytometric assay to analyze histone acetylation at single-cell level in human T cells. The data showed that histone acetylation was increased during T cell activation. Among T cell subsets, terminally differentiated effector memory T (TEMRA) cells robustly producing effector cytokines were hyper-acetylated. Conversely, these TEMRA cells had lower expression levels of TCF-1, a key transcription factor for maintaining stem cell features. Pharmaceutical inhibition of histone acetylation using a small molecule C646 restrained the production of effector molecules, but retained stem cell-like properties in T cells after expansion.
CONCLUSIONS: Per-cell histone acetylation is associated with terminal differentiation and poor stemness in human T cells. These observations suggest a new approach to enhance the stem cell-like properties of T cells and improve the efficacy of immunotherapy.

Keywords:  C646; Human T cell; Single-cell histone acetylation; Stemness; TCF-1; Terminal differentiation

DOI:  https://doi.org/10.1186/s13148-024-01634-w
Immun Ageing. 2024 Feb 05. 21(1): 13

The interplay between obesity, immunosenescence, and insulin resistance.

Ghazaleh Shimi, Mohammad Hassan Sohouli, Arman Ghorbani, Azam Shakery, Hamid Zand.

  Obesity, which is the accumulation of fat in adipose tissue, has adverse impacts on human health. Obesity-related metabolic dysregulation has similarities to the metabolic alterations observed in aging. It has been shown that the adipocytes of obese individuals undergo cellular aging, known as senescence. Senescence can be transmitted to other normal cells through a series of chemical factors referred to as the senescence-associated secretory phenotype (SASP). Most of these factors are pro-inflammatory compounds. The immune system removes these senescent T-cells, but immunosenescence, which is the senescence of immune cells, disrupts the clearance of senescent T-cells. Immunosenescence occurs as a result of aging or indirectly through transmission from senescent tissues. The significant occurrence of senescence in obesity is expected to cause immunosenescence and impairs the immune response to resolve inflammation. The sustained and chronic inflammation disrupts insulin's metabolic actions in metabolic tissues. Therefore, this review focuses on the role of senescent adipocyte cells in obesity-associated immunosenescence and subsequent metabolic dysregulation. Moreover, the article suggests novel therapeutic approaches to improve metabolic syndrome by targeting senescent T-cells or using senotherapeutics.

Keywords:  Immunosenescence; Inflammation; Insulin resistance; Obesity; Senescence; Senescence-associated secretory phenotype

DOI:  https://doi.org/10.1186/s12979-024-00414-7
bioRxiv. 2024 Jan 26. pii: 2024.01.22.576725. [Epub ahead of print]

Functional impairment of "helpless" CD8 + memory T cells is transient and driven by prolonged but finite cognate antigen presentation.

Verena van der Heide, Bennett Davenport, Beatrice Cubitt, Vladimir Roudko, Daniel Choo, Etienne Humblin, Kevin Jhun, Krista Angeliadis, Travis Dawson, Glaucia Furtado, Alice Kamphorst, Rafi Ahmed, Juan Carlos de la Torre, Dirk Homann.

Generation of functional CD8 + T cell memory typically requires engagement of CD4 + T cells. However, in certain scenarios, such as acutely-resolving viral infections, effector (T E ) and subsequent memory (T M ) CD8 + T cell formation appear impervious to a lack of CD4 + T cell help during priming. Nonetheless, such "helpless" CD8 + T M respond poorly to pathogen rechallenge. At present, the origin and long-term evolution of helpless CD8 + T cell memory remain incompletely understood. Here, we demonstrate that helpless CD8 + T E differentiation is largely normal but a multiplicity of helpless CD8 T M defects, consistent with impaired memory maturation, emerge as a consequence of prolonged yet finite exposure to cognate antigen. Importantly, these defects resolve over time leading to full restoration of CD8 + T M potential and recall capacity. Our findings provide a unified explanation for helpless CD8 + T cell memory and emphasize an unexpected CD8 + T M plasticity with implications for vaccination strategies and beyond.

DOI: https://doi.org/10.1101/2024.01.22.576725
Int J Mol Sci. 2024 Jan 23. pii: 1396. [Epub ahead of print]25(3):

Nanoparticle-Based Immunotherapy for Reversing T-Cell Exhaustion.

Fei Li, Yahong Wang, Dandan Chen, Yunjie Du.

  T-cell exhaustion refers to a state of T-cell dysfunction commonly observed in chronic infections and cancer. Immune checkpoint molecules blockading using PD-1 and TIM-3 antibodies have shown promising results in reversing exhaustion, but this approach has several limitations. The treatment of T-cell exhaustion is still facing great challenges, making it imperative to explore new therapeutic strategies. With the development of nanotechnology, nanoparticles have successfully been applied as drug carriers and delivery systems in the treatment of cancer and infectious diseases. Furthermore, nanoparticle-based immunotherapy has emerged as a crucial approach to reverse exhaustion. Here, we have compiled the latest advances in T-cell exhaustion, with a particular focus on the characteristics of exhaustion that can be targeted. Additionally, the emerging nanoparticle-based delivery systems were also reviewed. Moreover, we have discussed, in detail, nanoparticle-based immunotherapies that aim to reverse exhaustion, including targeting immune checkpoint blockades, remodeling the tumor microenvironment, and targeting the metabolism of exhausted T cells, etc. These data could aid in comprehending the immunopathogenesis of exhaustion and accomplishing the objective of preventing and treating chronic diseases or cancer.

Keywords:  T cell metabolism; T-cell exhaustion; immune checkpoint blockade; nanoparticle; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms25031396
iScience. 2024 Feb 16. 27(2): 108957

EP300 restores the glycolytic activity and anti-tumor function of CD8+ cytotoxic T cells in nasopharyngeal carcinoma.

Zhixiu Xia, Xiaoxu Ding, Chao Ji, Dabo Zhou, Xun Sun, Tiancong Liu.

  Competition for glucose may metabolically limit T cells during cancer progression. This study shows that culturing in the condition medium (CM) of NPC c6661 cells restricted glycolytic and immune activities of CD8+ T cells. These cells also exhibited limited tumor-eliminating effects in mouse xenograft tumor models. Glucose supplementation restored glycolysis and immune activity of CD8+ T cells in vitro and in vivo by rescuing the expression of E1A binding protein p300 (EP300). EP300 upregulated bromodomain PHD finger transcription factor (BPTF) expression by catalyzing H3K27ac modification, and BPTF further activated AT-rich interaction domain 1A (ARID1A) transcription. Either BPTF or ARID1A knockdown in CD8+ T cells reduced their glycolytic activity, decreased the secretion of cytotoxic molecules, and blocked the tumor-killing function in mice. Overall, this study demonstrates that EP300 restores the glycolytic and anti-tumor activities of CD8+ T cells in the glucose restriction condition in NPC through the BPTF/ARID1A axis.

Keywords:  Cancer; Cell biology; Immunology

DOI:  https://doi.org/10.1016/j.isci.2024.108957
Nat Cell Biol. 2024 Feb 07.

ECSIT facilitates memory CD8+ T cell development by mediating fumarate synthesis during viral infection and tumorigenesis.

Yongbing Yang, Yanan Wang, Zhongcheng Wang, Huanyu Yan, Yi Gong, Yingchao Hu, Yuying Jiang, Shuang Wen, Feifei Xu, Bingwei Wang, Fiachra Humphries, Yun Chen, Xi Wang, Shuo Yang.

Memory CD8+ T cells play a crucial role in infection and cancer and mount rapid responses to repeat antigen exposure. Although memory cell transcriptional programmes have been previously identified, the regulatory mechanisms that control the formation of CD8+ T cells have not been resolved. Here we report ECSIT as an essential mediator of memory CD8+ T cell differentiation. Ablation of ECSIT in T cells resulted in loss of fumarate synthesis and abrogated TCF-1 expression via demethylation of the TCF-1 promoter by the histone demethylase KDM5, thereby impairing memory CD8+ T cell development in a cell-intrinsic manner. In addition, ECSIT expression correlated positively with stem-like memory progenitor exhausted CD8+ T cells and the survival of patients with cancer. Our study demonstrates that ECSIT-mediated fumarate synthesis stimulates TCF-1 activity and memory CD8+ T cell development during viral infection and tumorigenesis and highlights the utility of therapeutic fumarate analogues and PD-L1 inhibition for tumour immunotherapy.

DOI: https://doi.org/10.1038/s41556-024-01351-9
Cell Rep. 2024 Feb 07. pii: S2211-1247(24)00074-3. [Epub ahead of print]43(2): 113746

Lactic acid induces transcriptional repression of macrophage inflammatory response via histone acetylation.

Weiwei Shi, Tiffany J Cassmann, Aditya Vijay Bhagwate, Taro Hitosugi, W K Eddie Ip.

  Lactic acid has emerged as an important modulator of immune cell function. It can be produced by both gut microbiota and the host metabolism at homeostasis and during disease states. The production of lactic acid in the gut microenvironment is vital for tissue homeostasis. In the present study, we examined how lactic acid integrates cellular metabolism to shape the epigenome of macrophages during pro-inflammatory response. We found that lactic acid serves as a primary fuel source to promote histone H3K27 acetylation, which allows the expression of immunosuppressive gene program including Nr4a1. Consequently, macrophage pro-inflammatory function was transcriptionally repressed. Furthermore, the histone acetylation induced by lactic acid promotes a form of long-term immunosuppression ("trained immunosuppression"). Pre-exposure to lactic acid induces lipopolysaccharide tolerance. These findings thus indicate that lactic acid sensing and its effect on chromatin remodeling in macrophages represent a key homeostatic mechanism that can provide a tolerogenic tissue microenvironment.

Keywords:  CP: Immunology; CP: Metabolism; epigenetic reprogramming; histone acetylation; immunosuppression; inflammation; inflammatory bowel disease; lactic acid; macrophage; metabolism; metabolite sensing; tissue microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2024.113746
Front Immunol. 2024 ;15 1340048

Single cell analysis revealed that two distinct, unique CD4+ T cell subsets were increased in the small intestinal intraepithelial lymphocytes of aged mice.

Yuki Yonemoto, Yasuhiro Nemoto, Ryo Morikawa, Nana Shibayama, Shigeru Oshima, Takashi Nagaishi, Tomohiro Mizutani, Go Ito, Satoru Fujii, Ryuichi Okamoto.

  Recent advances in research suggest that aging has a controllable chronic inflammatory disease aspect. Aging systemic T cells, which secrete pro-inflammatory factors, affect surrounding somatic cells, and accelerate the aging process through chronic inflammation, have attracted attention as potential therapeutic targets in aging. On the other hand, there are few reports on the aging of the intestinal immune system, which differs from the systemic immune system in many ways. In the current study, we investigated the age-related changes in the intestinal immune system, particularly in T cells. The most significant changes were observed in the CD4+ T cells in the small intestinal IEL, with a marked increase in this fraction in old mice and reduced expression of CD27 and CD28, which are characteristic of aging systemic T cells. The proliferative capacity of aging IEL CD4+ T cells was significantly more reduced than that of aging systemic T cells. Transcriptome analysis showed that the expression of inflammatory cytokines was not upregulated, whereas Cd8α, NK receptors, and Granzymes were upregulated in aging IEL CD4+ T cells. Functional analysis showed that aging IEL T cells had a higher cytotoxic function against intestinal tumor organoids in vitro than young IEL T cells. scRNAseq revealed that splenic T cells show a transition from naïve to memory T cells, whereas intestinal T cells show the emergence of a CD8αα+CD4+ T cell fraction in aged mice, which is rarely seen in young cells. Further analysis of the aging IEL CD4+ T cells showed that two unique subsets are increased that are distinct from the systemic CD4+ T cells. Subset 1 has a pro-inflammatory component, with expression of IFNγ and upregulation of NFkB signaling pathways. Subset 2 does not express IFNγ, but upregulates inhibitory molecules and nIEL markers. Expression of granzymes and Cd8a was common to both. These fractions were in opposite positions in the clustering by UMAP and had different TCR repertoires. They may be involved in the suppression of intestinal aging and longevity through anti-tumor immunity, elimination of senescent cells and stressed cells in the aging environment. This finding could be a breakthrough in aging research.

Keywords:  CD4 T cell; T cell aging; intestinal immunity; intraepithelial lymphocyte; scRNAseq

DOI:  https://doi.org/10.3389/fimmu.2024.1340048
J Biomed Sci. 2024 Feb 07. 31(1): 20

Rab37 mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion in lung cancer.

Wan-Ting Kuo, I-Ying Kuo, Hung-Chia Hsieh, Ssu-Ting Wu, Wu-Chou Su, Yi-Ching Wang.

  BACKGROUND: Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor expressed on the surface of T cells. High expression of PD-1 leads to T-cell dysfunction in the tumor microenvironment (TME). However, the mechanism of intracellular trafficking and plasma membrane presentation of PD-1 remains unclear.METHODS: Multiple databases of lung cancer patients were integratively analyzed to screen Rab proteins and potential immune-related signaling pathways. Imaging and various biochemical assays were performed in Jurkat T cells, splenocytes, and human peripheral blood mononuclear cells (PBMCs). Rab37 knockout mice and specimens of lung cancer patients were used to validate the concept.
RESULTS: Here, we identify novel mechanisms of intracellular trafficking and plasma membrane presentation of PD-1 mediated by Rab37 small GTPase to sustain T cell exhaustion, thereby leading to poor patient outcome. PD-1 colocalized with Rab37-specific vesicles of T cells in a GTP-dependent manner whereby Rab37 mediated dynamic trafficking and membrane presentation of PD-1. However, glycosylation mutant PD-1 delayed cargo recruitment to the Rab37 vesicles, thus stalling membrane presentation. Notably, T cell proliferation and activity were upregulated in tumor-infiltrating T cells from the tumor-bearing Rab37 knockout mice compared to those from wild type. Clinically, the multiplex immunofluorescence-immunohistochemical assay indicated that patients with high Rab37+/PD-1+/TIM3+/CD8+ tumor infiltrating T cell profile correlated with advanced tumor stages and poor overall survival. Moreover, human PBMCs from patients demonstrated high expression of Rab37, which positively correlated with elevated levels of PD-1+ and TIM3+ in CD8+ T cells exhibiting reduced tumoricidal activity.
CONCLUSIONS: Our results provide the first evidence that Rab37 small GTPase mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion, and the tumor promoting function of Rab37/PD-1 axis in T cells of TME in lung cancer. The expression profile of Rab37high/PD-1high/TIM3high in tumor-infiltrating CD8+ T cells is a biomarker for poor prognosis in lung cancer patients.

Keywords:  Lung cancer; Membrane trafficking; PD-1; Rab37; T cell

DOI:  https://doi.org/10.1186/s12929-024-01009-6
Cancer Res Commun. 2024 Feb 09.

Exhausted tumor-infiltrating CD39+CD103+ CD8+ T cells unveil potential for increased survival in human pancreatic cancer.

Laia Gorchs, Carlos Fernández-Moro, Ebba Asplund, Marlies Oosthoek, Martin Solders, Poya Ghorbani, Ernesto Sparrelid, Elena Rangelova, Matthias J Löhr, Helen Kaipe.

In pancreatic ductal adenocarcinoma, the infiltration of CD8+ T cells within the tumor microenvironment correlate with a favorable prognosis. However, a significant proportion of tumor-infiltrating T cells become trapped within the desmoplastic stroma and lack tumor reactivity. Here, we explored different T-cell subsets in pancreatic tumors and adjacent tissues. We identified a subset of CD8+ T cells, double positive (DP) for CD39 and CD103 in pancreatic tumors, which has recently been described to display tumor reactivity in other types of solid tumors. Interestingly, DP CD8+ T cells preferentially accumulated in central tumor tissues compared to paired peripheral tumor and adjacent non-tumor tissues. Consistent with an antigen encounter, DP CD8+ T cells demonstrated higher proliferative rates and displayed an exhausted phenotype, characterized by elevated expression of PD-1 and TIM-3, compared to CD39-CD103- CD8+ T cells. Additionally, DP CD8+ T cells exhibited higher expression levels of the tissue trafficking receptors CCR5 and CXCR6, while displaying lower levels of CXCR3 and CXCR4. Importantly, a high proportion of DP CD8+ T cells is associated with increased patient survival. These findings suggest that DP CD8+ T cells with a phenotype reminiscent of that of tumor-reactive T cells are present in pancreatic tumors. The abundance of DP CD8+ T cells could potentially aid in selecting patients for pancreatic cancer immunotherapy trials.

DOI: https://doi.org/10.1158/2767-9764.CRC-23-0405
bioRxiv. 2024 Jan 22. pii: 2024.01.22.576704. [Epub ahead of print]

Antigen-specific age-related memory CD8 T cells induce and track Alzheimer's-like neurodegeneration.

Akanksha Panwar, Altan Rentsendorj, Michelle Jhun, Robert M Cohen, Ryan Cordner, Nicole Gull, Robert N Pechnick, Gretchen Duvall, Armen Mardiros, David Golchian, Hannah Schubloom, Lee-Way Jin, Debby Van Dam, Yannick Vermeiren, Hans De Reu, Peter Paul De Deyn, Jevgenij A Raskatov, Keith L Black, Dwain K Irvin, Brian A Williams, Christopher J Wheeler.

Cerebral (Aβ) plaque and (pTau) tangle deposition are hallmarks of Alzheimer's disease (AD), yet are insufficient to confer complete AD-like neurodegeneration experimentally. Factors acting upstream of Aβ/pTau in AD remain unknown, but their identification could enable earlier diagnosis and more effective treatments. T cell abnormalities are emerging AD hallmarks, and CD8 T cells were recently found to mediate neurodegeneration downstream of tangle deposition in hereditary neurodegeneration models. The precise impact of T cells downstream of Aβ/fibrillar pTau, however, appears to vary depending on the animal model used. Our prior work suggested that antigen-specific memory CD8 T (" hi T") cells act upstream of Aβ/pTau after brain injury. Here we examine whether hi T cells influence sporadic AD-like pathophysiology upstream of Aβ/pTau. Examining neuropathology, gene expression, and behavior in our hi T mouse model we show that CD8 T cells induce plaque and tangle-like deposition, modulate AD-related genes, and ultimately result in progressive neurodegeneration with both gross and fine features of sporadic human AD. T cells required Perforin to initiate this pathophysiology, and IFNγ for most gene expression changes and progression to more widespread neurodegenerative disease. Analogous antigen-specific memory CD8 T cells were significantly elevated in the brains of human AD patients, and their loss from blood corresponded to sporadic AD and related cognitive decline better than plasma pTau-217, a promising AD biomarker candidate. Our work is the first to identify an age-related factor acting upstream of Aβ/pTau to initiate AD-like pathophysiology, the mechanisms promoting its pathogenicity, and its relevance to human sporadic AD.Significance Statement: This study changes our view of Alzheimer's Disease (AD) initiation and progression. Mutations promoting cerebral beta-amyloid (Aβ) deposition guarantee rare genetic forms of AD. Thus, the prevailing hypothesis has been that Aβ is central to initiation and progression of all AD, despite contrary animal and patient evidence. We show that age-related T cells generate neurodegeneration with compelling features of AD in mice, with distinct T cell functions required for pathological initiation and neurodegenerative progression. Knowledge from these mice was applied to successfully predict previously unknown features of human AD and generate novel tools for its clinical management.

DOI: https://doi.org/10.1101/2024.01.22.576704