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Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease 期刊论文
NATURE, 2020, 577 (7790) : 399-+
作者:  Gate, David;  Saligrama, Naresha;  Leventhal, Olivia;  Yang, Andrew C.;  Unger, Michael S.;  Middeldorp, Jinte;  Chen, Kelly;  Lehallier, Benoit;  Channappa, Divya;  De Los Santos, Mark B.;  McBride, Alisha;  Pluvinage, John;  Elahi, Fanny;  Tam, Grace Kyin-Ye;  Kim, Yongha;  Greicius, Michael;  Wagner, Anthony D.;  Aigner, Ludwig;  Galasko, Douglas R.;  Davis, Mark M.;  Wyss-Coray, Tony
收藏  |  浏览/下载:38/0  |  提交时间:2020/07/03

Alzheimer'  s disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function(1). However, little is known about the contribution of the adaptive immune response in Alzheimer'  s disease(2). Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer'  s disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer'  s disease that consists of increased numbers of CD8(+) T effector memory CD45RA(+) (T-EMRA) cells. In a second cohort, we found that CD8(+) T-EMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8(+) T-EMRA cells in the cerebrospinal fluid of patients with Alzheimer'  s disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer'  s disease to two separate Epstein-Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer'  s disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.


  
An acute immune response underlies the benefit of cardiac stem cell therapy 期刊论文
NATURE, 2020, 577 (7790) : 405-+
作者:  Schmacke, Niklas A.;  Hornung, Veit
收藏  |  浏览/下载:38/0  |  提交时间:2020/07/03

Clinical trials using adult stem cells to regenerate damaged heart tissue continue to this day(1,2), despite ongoing questions of efficacy and a lack of mechanistic understanding of the underlying biological effect(3). The rationale for these cell therapy trials is derived from animal studies that show a modest but reproducible improvement in cardiac function in models of cardiac ischaemic injury(4,5). Here we examine the mechanistic basis for cell therapy in mice after ischaemia-reperfusion injury, and find that-although heart function is enhanced-it is not associated with the production of new cardiomyocytes. Cell therapy improved heart function through an acute sterile immune response characterized by the temporal and regional induction of CCR2(+) and CX3CR1(+) macrophages. Intracardiac injection of two distinct types of adult stem cells, cells killed by freezing and thawing or a chemical inducer of the innate immune response all induced a similar regional accumulation of CCR2(+) and CX3CR1(+) macrophages, and provided functional rejuvenation to the heart after ischaemia-reperfusion injury. This selective macrophage response altered the activity of cardiac fibroblasts, reduced the extracellular matrix content in the border zone and enhanced the mechanical properties of the injured area. The functional benefit of cardiac cell therapy is thus due to an acute inflammatory-based wound-healing response that rejuvenates the infarcted area of the heart.


  
C9orf72 suppresses systemic and neural inflammation induced by gut bacteria 期刊论文
NATURE, 2020
作者:  Nikoo, Mohammad Samizadeh;  Jafari, Armin;  Perera, Nirmana;  Zhu, Minghua;  Santoruvo, Giovanni;  Matioli, Elison
收藏  |  浏览/下载:34/0  |  提交时间:2020/07/03

A hexanucleotide-repeat expansion in C9ORF72 is the most common genetic variant that contributes to amyotrophic lateral sclerosis and frontotemporal dementia(1,2). The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration(3-9). The expansion is transcribed into a long repetitive RNA, which negatively sequesters RNA-binding proteins(5) before its non-canonical translation into neural-toxic dipeptide proteins(3,4). The failure of RNA polymerase to read through the mutation also reduces the abundance of the endogenous C9ORF72 gene product, which functions in endolysosomal pathways and suppresses systemic and neural inflammation(6-9). Notably, the effects of the repeat expansion act with incomplete penetrance in families with a high prevalence of amyotrophic lateral sclerosis or frontotemporal dementia, indicating that either genetic or environmental factors modify the risk of disease for each individual. Identifying disease modifiers is of considerable translational interest, as it could suggest strategies to diminish the risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, or to slow progression. Here we report that an environment with reduced abundance of immune-stimulating bacteria(10,11) protects C9orf72-mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathological inflammatory response, we found that reducing the microbial burden in mutant mice with broad spectrum antibiotics-as well as transplanting gut microflora from a protective environment-attenuated inflammatory phenotypes, even after their onset. Our studies provide further evidence that the microbial composition of our gut has an important role in brain health and can interact in surprising ways with well-known genetic risk factors for disorders of the nervous system.


Reduced abundance of immune-stimulating gut bacteria ameliorated the inflammatory and autoimmune phenotypes of mice with mutations in C9orf72, which in the human orthologue are linked to amyotrophic lateral sclerosis and frontotemporal dementia.


  
Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I 期刊论文
NATURE, 2020, 581 (7806) : 100-+
作者:  Waszak, Sebastian M.;  Robinson, Giles W.;  Gudenas, Brian L.;  Smith, Kyle S.;  Forget, Antoine;  Kojic, Marija;  Garcia-Lopez, Jesus;  Hadley, Jennifer;  Hamilton, Kayla V.;  Indersie, Emilie;  Buchhalter, Ivo;  Kerssemakers, Jules;  Jager, Natalie;  Sharma, Tanvi;  Rausch, Tobias;  Kool, Marcel;  Sturm, Dominik;  Jones, David T. W.;  Vasilyeva, Aksana;  Tatevossian, Ruth G.;  Neale, Geoffrey;  Lombard, Berangere;  Loew, Damarys;  Nakitandwe, Joy;  Rusch, Michael;  Bowers, Daniel C.;  Bendel, Anne;  Partap, Sonia;  Chintagumpala, Murali;  Crawford, John;  Gottardo, Nicholas G.;  Smith, Amy;  Dufour, Christelle;  Rutkowski, Stefan;  Eggen, Tone;  Wesenberg, Finn;  Kjaerheim, Kristina;  Feychting, Maria;  Lannering, Birgitta;  Schuz, Joachim;  Johansen, Christoffer;  Andersen, Tina V.;  Roosli, Martin;  Kuehni, Claudia E.;  Grotzer, Michael;  Remke, Marc;  Puget, Stephanie;  Pajtler, Kristian W.;  Milde, Till;  Witt, Olaf;  Ryzhova, Marina;  Korshunov, Andrey;  Orr, Brent A.;  Ellison, David W.;  Brugieres, Laurence;  Lichter, Peter;  Nichols, Kim E.;  Gajjar, Amar;  Wainwright, Brandon J.;  Ayrault, Olivier;  Korbel, Jan O.;  Northcott, Paul A.;  Pfister, Stefan M.
收藏  |  浏览/下载:61/0  |  提交时间:2020/07/03

Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy(1-3). However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found(5) despite the frequent downregulation of MHC-I expression(6-8). Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8(+) T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.


Inhibition of the autophagy-lysosome system upregulates surface expression of MHC class I proteins and enhances antigen presentation, and evokes a potent anti-tumour immune response that is mediated by CD8(+) T cells.


  
Olfactory sniffing signals consciousness in unresponsive patients with brain injuries 期刊论文
NATURE, 2020
作者:  Hellmuth, Susanne;  Gomez-H, Laura;  Pendas, Alberto M.;  Stemmann, Olaf
收藏  |  浏览/下载:19/0  |  提交时间:2020/07/03

After severe brain injury, it can be difficult to determine the state of consciousness of a patient, to determine whether the patient is unresponsive or perhaps minimally conscious(1), and to predict whether they will recover. These diagnoses and prognoses are crucial, as they determine therapeutic strategies such as pain management, and can underlie end-of-life decisions(2,3). Nevertheless, there is an error rate of up to 40% in determining the state of consciousness in patients with brain injuries(4,5). Olfaction relies on brain structures that are involved in the basic mechanisms of arousal(6), and we therefore hypothesized that it may serve as a biomarker for consciousness(7). Here we use a non-verbal non-task-dependent measure known as the sniff response(8-11) to determine consciousness in patients with brain injuries. By measuring odorant-dependent sniffing, we gain a sensitive measure of olfactory function(10-15). We measured the sniff response repeatedly over time in patients with severe brain injuries and found that sniff responses significantly discriminated between unresponsive and minimally conscious states at the group level. Notably, at the single-patient level, if an unresponsive patient had a sniff response, this assured future regaining of consciousness. In addition, olfactory sniff responses were associated with long-term survival rates. These results highlight the importance of olfaction in human brain function, and provide an accessible tool that signals consciousness and recovery in patients with brain injuries.


Odorant-dependent sniff responses predicted the long-term survival rates of patients with severe brain injury, and discriminated between individuals who were unresponsive and in minimally conscious states.


  
AIM2 inflammasome surveillance of DNA damage shapes neurodevelopment 期刊论文
NATURE, 2020, 580 (7805) : 647-+
作者:  Okada, Tatsuaki;  Fukuhara, Tetsuya;  Tanaka, Satoshi;  Taguchi, Makoto;  Arai, Takehiko;  Senshu, Hiroki;  Sakatani, Naoya;  Shimaki, Yuri;  Demura, Hirohide;  Ogawa, Yoshiko;  Suko, Kentaro;  Sekiguchi, Tomohiko;  Kouyama, Toru;  Takita, Jun;  Matsunaga, Tsuneo;  Imamura, Takeshi;  Wada, Takehiko;  Hasegawa, Sunao;  Helbert, Joern;  Mueller, Thomas G.;  Hagermann, Axel;  Biele, Jens;  Grott, Matthias;  Hamm, Maximilian;  Delbo, Marco;  Hirata, Naru;  Hirata, Naoyuki;  Yamamoto, Yukio;  Sugita, Seiji;  Namiki, Noriyuki;  Kitazato, Kohei;  Arakawa, Masahiko;  Tachibana, Shogo;  Ikeda, Hitoshi;  Ishiguro, Masateru;  Wada, Koji;  Honda, Chikatoshi;  Honda, Rie;  Ishihara, Yoshiaki;  Matsumoto, Koji;  Matsuoka, Moe;  Michikami, Tatsuhiro;  Miura, Akira;  Morota, Tomokatsu;  Noda, Hirotomo;  Noguchi, Rina;  Ogawa, Kazunori;  Shirai, Kei;  Tatsumi, Eri;  Yabuta, Hikaru;  Yokota, Yasuhiro;  Yamada, Manabu;  Abe, Masanao;  Hayakawa, Masahiko;  Iwata, Takahiro;  Ozaki, Masanobu;  Yano, Hajime;  Hosoda, Satoshi;  Mori, Osamu;  Sawada, Hirotaka;  Shimada, Takanobu;  Takeuchi, Hiroshi;  Tsukizaki, Ryudo;  Fujii, Atsushi;  Hirose, Chikako;  Kikuchi, Shota;  Mimasu, Yuya;  Ogawa, Naoko;  Ono, Go;  Takahashi, Tadateru;  Takei, Yuto;  Yamaguchi, Tomohiro;  Yoshikawa, Kent;  Terui, Fuyuto;  Saiki, Takanao;  Nakazawa, Satoru;  Yoshikawa, Makoto;  Watanabe, Seiichiro;  Tsuda, Yuichi
收藏  |  浏览/下载:46/0  |  提交时间:2020/07/03

The sensing of DNA damage by the AIM2 inflammasome promotes the death of central nervous system cells and is required for normal brain development.


Neurodevelopment is characterized by rapid rates of neural cell proliferation and differentiation followed by massive cell death in which more than half of all recently generated brain cells are pruned back. Large amounts of DNA damage, cellular debris, and by-products of cellular stress are generated during these neurodevelopmental events, all of which can potentially activate immune signalling. How the immune response to this collateral damage influences brain maturation and function remains unknown. Here we show that the AIM2 inflammasome contributes to normal brain development and that disruption of this immune sensor of genotoxic stress leads to behavioural abnormalities. During infection, activation of the AIM2 inflammasome in response to double-stranded DNA damage triggers the production of cytokines as well as a gasdermin-D-mediated form of cell death known as pyroptosis(1-4). We observe pronounced AIM2 inflammasome activation in neurodevelopment and find that defects in this sensor of DNA damage result in anxiety-related behaviours in mice. Furthermore, we show that the AIM2 inflammasome contributes to central nervous system (CNS) homeostasis specifically through its regulation of gasdermin-D, and not via its involvement in the production of the cytokines IL-1 and/or IL-18. Consistent with a role for this sensor of genomic stress in the purging of genetically compromised CNS cells, we find that defective AIM2 inflammasome signalling results in decreased neural cell death both in response to DNA damage-inducing agents and during neurodevelopment. Moreover, mutations in AIM2 lead to excessive accumulation of DNA damage in neurons as well as an increase in the number of neurons that incorporate into the adult brain. Our findings identify the inflammasome as a crucial player in establishing a properly formed CNS through its role in the removal of genetically compromised cells.


  
A conserved dendritic-cell regulatory program limits antitumour immunity 期刊论文
NATURE, 2020, 580 (7802) : 257-+
作者:  Perry, Rachel J.;  Zhang, Dongyan;  Guerra, Mateus T.;  Brill, Allison L.;  Goedeke, Leigh;  Nasiri, Ali R.;  Rabin-Court, Aviva;  Wang, Yongliang;  Peng, Liang;  Dufour, Sylvie;  Zhang, Ye;  Zhang, Xian-Man;  Butrico, Gina M.;  Toussaint, Keshia;  Nozaki, Yuichi;  Cline, Gary W.;  Petersen, Kitt Falk;  Nathanson, Michael H.;  Ehrlich, Barbara E.;  Shulman, Gerald I.
收藏  |  浏览/下载:54/0  |  提交时间:2020/07/03

After taking up tumour-associated antigens, dendritic cells in mouse and human tumours upregulate a regulatory gene program that limits dendritic cell immunostimulatory function, and modulating this program can rescue antitumor immunity in mice.


Checkpoint blockade therapies have improved cancer treatment, but such immunotherapy regimens fail in a large subset of patients. Conventional type 1 dendritic cells (DC1s) control the response to checkpoint blockade in preclinical models and are associated with better overall survival in patients with cancer, reflecting the specialized ability of these cells to prime the responses of CD8(+) T cells(1-3). Paradoxically, however, DC1s can be found in tumours that resist checkpoint blockade, suggesting that the functions of these cells may be altered in some lesions. Here, using single-cell RNA sequencing in human and mouse non-small-cell lung cancers, we identify a cluster of dendritic cells (DCs) that we name '  mature DCs enriched in immunoregulatory molecules'  (mregDCs), owing to their coexpression of immunoregulatory genes (Cd274, Pdcd1lg2 and Cd200) and maturation genes (Cd40, Ccr7 and Il12b). We find that the mregDC program is expressed by canonical DC1s and DC2s upon uptake of tumour antigens. We further find that upregulation of the programmed death ligand 1 protein-a key checkpoint molecule-in mregDCs is induced by the receptor tyrosine kinase AXL, while upregulation of interleukin (IL)-12 depends strictly on interferon-gamma and is controlled negatively by IL-4 signalling. Blocking IL-4 enhances IL-12 production by tumour-antigen-bearing mregDC1s, expands the pool of tumour-infiltrating effector T cells and reduces tumour burden. We have therefore uncovered a regulatory module associated with tumour-antigen uptake that reduces DC1 functionality in human and mouse cancers.


  
Germline Elongator mutations in Sonic Hedgehog medulloblastoma 期刊论文
NATURE, 2020, 580 (7803) : 396-+
作者:  Helmrich, S.;  Arias, A.;  Lochead, G.;  Wintermantel, T. M.;  Buchhold, M.;  Diehl, S.;  Whitlock, S.
收藏  |  浏览/下载:32/0  |  提交时间:2020/07/03

Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children(1,2), and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma(3). Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHH alpha subtype(4) and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U-34) position(5,6). Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems(7-9). Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.


  
Gasdermin E suppresses tumour growth by activating anti-tumour immunity 期刊论文
NATURE, 2020
作者:  Maroju, Praveen Kumar;  Grazioli, Cesare;  Di Fraia, Michele;  Moioli, Matteo;  Ertel, Dominik;  Ahmadi, Hamed;  Plekan, Oksana;  Finetti, Paola;  Allaria, Enrico;  Giannessi, Luca;  De Ninno, Giovanni;  Spezzani, Carlo;  Penco, Giuseppe;  Spampinati, Simone;  Demidovich, Alexander
收藏  |  浏览/下载:61/0  |  提交时间:2020/07/03

Cleavage of the gasdermin proteins to produce pore-forming amino-terminal fragments causes inflammatory cell death (pyroptosis)(1). Gasdermin E (GSDME, also known as DFNA5)-mutated in familial ageing-related hearing loss(2)-can be cleaved by caspase 3, thereby converting noninflammatory apoptosis to pyroptosis in GSDME-expressing cells(3-5). GSDME expression is suppressed in many cancers, and reduced GSDME levels are associated with decreased survival as a result of breast cancer(2,6), suggesting that GSDME might be a tumour suppressor. Here we show that 20 of 22 tested cancer-associated GSDME mutations reduce GSDME function. In mice, knocking out Gsdme in GSDME-expressing tumours enhances, whereas ectopic expression in Gsdme-repressed tumours inhibits, tumour growth. This tumour suppression is mediated by killer cytotoxic lymphocytes: it is abrogated in perforin-deficient mice or mice depleted of killer lymphocytes. GSDME expression enhances the phagocytosis of tumour cells by tumour-associated macrophages, as well as the number and functions of tumour-infiltrating natural-killer and CD8(+) T lymphocytes. Killer-cell granzyme B also activates caspase-independent pyroptosis in target cells by directly cleaving GSDME at the same site as caspase 3. Uncleavable or pore-defective GSDME proteins are not tumour suppressive. Thus, tumour GSDME acts as a tumour suppressor by activating pyroptosis, enhancing anti-tumour immunity.


The gasdermin E protein is shown to act as a tumour suppressor: it is cleaved by caspase 3 and granzyme B and leads to pyroptosis of cancer cells, provoking an immune response to the tumour.


  
Large Earthquake Reshapes the Groundwater Flow System: Insight From the Water-Level Response to Earth Tides and Atmospheric Pressure in a Deep Well 期刊论文
WATER RESOURCES RESEARCH, 2019, 55 (5) : 4207-4219
作者:  Zhang, H.;  Shi, Z.;  Wang, G.;  Sun, X.;  Yan, R.;  Liu, C.
收藏  |  浏览/下载:18/0  |  提交时间:2019/11/26
earth tides  barometric response function  aquifer  aquitard  water level