The Kinase Activity of Hematopoietic Progenitor Kinase 1 Is Essential for the Regulation of T Cell Function.


:We examined hematopoietic protein kinase 1 (HPK1), whose reliance on scaffold versus kinase functions for negative immune cell regulation is poorly understood and critical to its assessment as a viable drug target. We identify kinase-dependent roles for HPK1 in CD8 T cells that restrict their anti-viral and anti-tumor responses by using HPK1 kinase-dead (HPK1.kd) knockin mice. Loss of HPK1 kinase function enhanced T cell receptor signaling and cytokine secretion in a T-cell-intrinsic manner. In response to chronic lymphocytic choriomeningitis virus (LCMV) infection or tumor challenge, viral clearance and tumor growth inhibition were enhanced in HPK1.kd mice, accompanied by an increase in effector CD8 T cell function. Co-blockade of PD-L1 further enhanced T effector cell function, resulting in superior anti-viral and anti-tumor immunity over single target blockade. These results identify the importance of HPK1 kinase activity in the negative regulation of CD8 effector functions, implicating its potential as a cancer immunotherapy target.


Cell Rep


Cell reports


Hernandez S,Qing J,Thibodeau RH,Du X,Park S,Lee HM,Xu M,Oh S,Navarro A,Roose-Girma M,Newman RJ,Warming S,Nannini M,Sampath D,Kim JM,Grogan JL,Mellman I




Has Abstract


2018-10-02 00:00:00












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    abstract::The efficient generation of hematopoietic stem cells from human pluripotent stem cells is dependent on the appropriate specification of the definitive hematopoietic program during differentiation. In this study, we used T lymphocyte potential to track the onset of definitive hematopoiesis from human embryonic and indu...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Kennedy M,Awong G,Sturgeon CM,Ditadi A,LaMotte-Mohs R,Zúñiga-Pflücker JC,Keller G

    更新日期:2012-12-27 00:00:00

  • Enhancement of BLM-DNA2-Mediated Long-Range DNA End Resection by CtIP.

    abstract::DNA double-strand break repair by homologous recombination entails the resection of DNA ends to reveal ssDNA tails, which are used to invade a homologous DNA template. CtIP and its yeast ortholog Sae2 regulate the nuclease activity of MRE11 in the initial stage of resection. Deletion of CtIP in the mouse or SAE2 in ye...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Daley JM,Jimenez-Sainz J,Wang W,Miller AS,Xue X,Nguyen KA,Jensen RB,Sung P

    更新日期:2017-10-10 00:00:00

  • Conserved Herpesvirus Protein Kinases Target SAMHD1 to Facilitate Virus Replication.

    abstract::To ensure a successful infection, herpesviruses have developed elegant strategies to counterbalance the host anti-viral responses. Sterile alpha motif and HD domain 1 (SAMHD1) was recently identified as an intrinsic restriction factor for a variety of viruses. Aside from HIV-2 and the related simian immunodeficiency v...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Zhang K,Lv DW,Li R

    更新日期:2019-07-09 00:00:00

  • Terminal Nerve GnRH3 Neurons Mediate Slow Avoidance of Carbon Dioxide in Larval Zebrafish.

    abstract::Escape responses to threatening stimuli are vital for survival in all animal species. Larval zebrafish display fast escape responses when exposed to tactile, acoustic, and visual stimuli. However, their behavioral responses to chemosensory stimuli remain unknown. In this study, we found that carbon dioxide (CO2) induc...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Koide T,Yabuki Y,Yoshihara Y

    更新日期:2018-01-30 00:00:00

  • Cdk4 and Cdk6 Couple the Cell-Cycle Machinery to Cell Growth via mTORC1.

    abstract::Cell growth is coupled to cell-cycle progression in mitotically proliferating mammalian cells, but the underlying molecular mechanisms are not well understood. CyclinD-Cdk4/6 is known to phosphorylate RB to promote S-phase entry, but recent work suggests they have additional functions. We show here that CyclinD-Cdk4/6...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Romero-Pozuelo J,Figlia G,Kaya O,Martin-Villalba A,Teleman AA

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  • The Release of Adipose Stromal Cells from Subcutaneous Adipose Tissue Regulates Ectopic Intramuscular Adipocyte Deposition.

    abstract::Ectopic lipid deposition (ELD) is defined by excess fat storage in locations not classically associated with adipose tissue (AT) storage. ELD is positively correlated with insulin resistance and increased risk of metabolic disorders. ELD appears as lipid droplets or adipocytes, whose cell origin is unknown. We previou...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Girousse A,Gil-Ortega M,Bourlier V,Bergeaud C,Sastourné-Arrey Q,Moro C,Barreau C,Guissard C,Vion J,Arnaud E,Pradère JP,Juin N,Casteilla L,Sengenès C

    更新日期:2019-04-09 00:00:00

  • The Balance between Mono- and NEDD8-Chains Controlled by NEDP1 upon DNA Damage Is a Regulatory Module of the HSP70 ATPase Activity.

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    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Bailly AP,Perrin A,Serrano-Macia M,Maghames C,Leidecker O,Trauchessec H,Martinez-Chantar ML,Gartner A,Xirodimas DP

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  • RNAi screening reveals proteasome- and Cullin3-dependent stages in vaccinia virus infection.

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    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Mercer J,Snijder B,Sacher R,Burkard C,Bleck CK,Stahlberg H,Pelkmans L,Helenius A

    更新日期:2012-10-25 00:00:00

  • Aging Triggers a Repressive Chromatin State at Bdnf Promoters in Hippocampal Neurons.

    abstract::Cognitive capacities decline with age, an event accompanied by the altered transcription of synaptic plasticity genes. Here, we show that the transcriptional induction of Bdnf by a mnemonic stimulus is impaired in aged hippocampal neurons. Mechanistically, this defect is due to reduced NMDA receptor (NMDAR)-mediated a...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Palomer E,Martín-Segura A,Baliyan S,Ahmed T,Balschun D,Venero C,Martin MG,Dotti CG

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    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Gromova KV,Muhia M,Rothammer N,Gee CE,Thies E,Schaefer I,Kress S,Kilimann MW,Shevchuk O,Oertner TG,Kneussel M

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  • Data-Driven Modeling of Intracellular Auxin Fluxes Indicates a Dominant Role of the ER in Controlling Nuclear Auxin Uptake.

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    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Middleton AM,Dal Bosco C,Chlap P,Bensch R,Harz H,Ren F,Bergmann S,Wend S,Weber W,Hayashi KI,Zurbriggen MD,Uhl R,Ronneberger O,Palme K,Fleck C,Dovzhenko A

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  • MERVL/Zscan4 Network Activation Results in Transient Genome-wide DNA Demethylation of mESCs.

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    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Eckersley-Maslin MA,Svensson V,Krueger C,Stubbs TM,Giehr P,Krueger F,Miragaia RJ,Kyriakopoulos C,Berrens RV,Milagre I,Walter J,Teichmann SA,Reik W

    更新日期:2016-09-27 00:00:00

  • Macrophage Exosomes Resolve Atherosclerosis by Regulating Hematopoiesis and Inflammation via MicroRNA Cargo.

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    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Bouchareychas L,Duong P,Covarrubias S,Alsop E,Phu TA,Chung A,Gomes M,Wong D,Meechoovet B,Capili A,Yamamoto R,Nakauchi H,McManus MT,Carpenter S,Van Keuren-Jensen K,Raffai RL

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  • XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation.

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    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Yabal M,Müller N,Adler H,Knies N,Groß CJ,Damgaard RB,Kanegane H,Ringelhan M,Kaufmann T,Heikenwälder M,Strasser A,Groß O,Ruland J,Peschel C,Gyrd-Hansen M,Jost PJ

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  • Progesterone Prevents High-Grade Serous Ovarian Cancer by Inducing Necroptosis of p53-Defective Fallopian Tube Epithelial Cells.

    abstract::High-grade serous ovarian carcinoma (HGSOC) originates mainly from the fallopian tube (FT) epithelium and always carries early TP53 mutations. We previously reported that tumors initiate in the FT fimbria epithelium because of apoptotic failure and the expansion of cells with DNA double-strand breaks (DSB) caused by b...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Wu NY,Huang HS,Chao TH,Chou HM,Fang C,Qin CZ,Lin CY,Chu TY,Zhou HH

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  • The Ciliary Protein Arl13b Functions Outside of the Primary Cilium in Shh-Mediated Axon Guidance.

    abstract::The small GTPase Arl13b is enriched in primary cilia and regulates Sonic hedgehog (Shh) signaling. During neural development, Shh controls patterning and proliferation through a canonical, transcription-dependent pathway that requires the primary cilium. Additionally, Shh controls axon guidance through a non-canonical...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Ferent J,Constable S,Gigante ED,Yam PT,Mariani LE,Legué E,Liem KF Jr,Caspary T,Charron F

    更新日期:2019-12-10 00:00:00

  • Cell-to-Cell Heterogeneity in p38-Mediated Cross-Inhibition of JNK Causes Stochastic Cell Death.

    abstract::The stress-activated protein kinases c-Jun N-terminal kinase (JNK) and p38 are important players in cell-fate decisions in response to environmental stress signals. Crosstalk signaling between JNK and p38 is emerging as an important regulatory mechanism in inflammatory and stress responses. However, it is unknown how ...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Miura H,Kondo Y,Matsuda M,Aoki K

    更新日期:2018-09-04 00:00:00

  • Single-Cell RNA-Sequencing-Based CRISPRi Screening Resolves Molecular Drivers of Early Human Endoderm Development.

    abstract::Studies in vertebrates have outlined conserved molecular control of definitive endoderm (END) development. However, recent work also shows that key molecular aspects of human END regulation differ even from rodents. Differentiation of human embryonic stem cells (ESCs) to END offers a tractable system to study the mole...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Genga RMJ,Kernfeld EM,Parsi KM,Parsons TJ,Ziller MJ,Maehr R

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  • Dynamic and Asymmetric Changes of the Microbial Communities after Cohousing in Laboratory Mice.

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    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Caruso R,Ono M,Bunker ME,Núñez G,Inohara N

    更新日期:2019-06-11 00:00:00

  • Fusion of Reprogramming Factors Alters the Trajectory of Somatic Lineage Conversion.

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    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Velychko S,Kang K,Kim SM,Kwak TH,Kim KP,Park C,Hong K,Chung C,Hyun JK,MacCarthy CM,Wu G,Schöler HR,Han DW

    更新日期:2019-04-02 00:00:00

  • Prdm16 Deficiency Leads to Age-Dependent Cardiac Hypertrophy, Adverse Remodeling, Mitochondrial Dysfunction, and Heart Failure.

    abstract::Hypertrophic cardiomyopathy (HCM) is a well-established risk factor for cardiovascular mortality worldwide. Although hypertrophy is traditionally regarded as an adaptive response to physiological or pathological stress, prolonged hypertrophy can lead to heart failure. Here we demonstrate that Prdm16 is dispensable for...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Cibi DM,Bi-Lin KW,Shekeran SG,Sandireddy R,Tee N,Singh A,Wu Y,Srinivasan DK,Kovalik JP,Ghosh S,Seale P,Singh MK

    更新日期:2020-10-20 00:00:00

  • Combinatorial Smad2/3 Activities Downstream of Nodal Signaling Maintain Embryonic/Extra-Embryonic Cell Identities during Lineage Priming.

    abstract::Epiblast cells in the early post-implantation stage mammalian embryo undergo a transition described as lineage priming before cell fate allocation, but signaling pathways acting upstream remain ill defined. Genetic studies demonstrate that Smad2/3 double-mutant mouse embryos die shortly after implantation. To learn mo...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Senft AD,Costello I,King HW,Mould AW,Bikoff EK,Robertson EJ

    更新日期:2018-08-21 00:00:00

  • AMPK modulates tissue and organismal aging in a non-cell-autonomous manner.

    abstract::AMPK exerts prolongevity effects in diverse species; however, the tissue-specific mechanisms involved are poorly understood. Here, we show that upregulation of AMPK in the adult Drosophila nervous system induces autophagy both in the brain and also in the intestinal epithelium. Induction of autophagy is linked to impr...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Ulgherait M,Rana A,Rera M,Graniel J,Walker DW

    更新日期:2014-09-25 00:00:00

  • Transcriptional Signatures of Tau and Amyloid Neuropathology.

    abstract::Alzheimer's disease (AD) is associated with the intracellular aggregation of hyperphosphorylated tau and the accumulation of β-amyloid in the neocortex. We use transgenic mice harboring human tau (rTg4510) and amyloid precursor protein (J20) mutations to investigate transcriptional changes associated with the progress...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Castanho I,Murray TK,Hannon E,Jeffries A,Walker E,Laing E,Baulf H,Harvey J,Bradshaw L,Randall A,Moore K,O'Neill P,Lunnon K,Collier DA,Ahmed Z,O'Neill MJ,Mill J

    更新日期:2020-02-11 00:00:00

  • Two mechanisms produce mutation hotspots at DNA breaks in Escherichia coli.

    abstract::Mutation hotspots and showers occur across phylogeny and profoundly influence genome evolution, yet the mechanisms that produce hotspots remain obscure. We report that DNA double-strand breaks (DSBs) provoke mutation hotspots via stress-induced mutation in Escherichia coli. With tet reporters placed 2 kb to 2 Mb (half...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Shee C,Gibson JL,Rosenberg SM

    更新日期:2012-10-25 00:00:00

  • Activation of CDK4 Triggers Development of Non-alcoholic Fatty Liver Disease.

    abstract::The development of non-alcoholic fatty liver disease (NAFLD) is a multiple step process. Here, we show that activation of cdk4 triggers the development of NAFLD. We found that cdk4 protein levels are elevated in mouse models of NAFLD and in patients with fatty livers. This increase leads to C/EBPα phosphorylation on S...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Jin J,Valanejad L,Nguyen TP,Lewis K,Wright M,Cast A,Stock L,Timchenko L,Timchenko NA

    更新日期:2016-07-19 00:00:00

  • TRIM28 Controls a Gene Regulatory Network Based on Endogenous Retroviruses in Human Neural Progenitor Cells.

    abstract::Endogenous retroviruses (ERVs), which make up 8% of the human genome, have been proposed to participate in the control of gene regulatory networks. In this study, we find a region- and developmental stage-specific expression pattern of ERVs in the developing human brain, which is linked to a transcriptional network ba...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Brattås PL,Jönsson ME,Fasching L,Nelander Wahlestedt J,Shahsavani M,Falk R,Falk A,Jern P,Parmar M,Jakobsson J

    更新日期:2017-01-03 00:00:00

  • Severe Malaria Infections Impair Germinal Center Responses by Inhibiting T Follicular Helper Cell Differentiation.

    abstract::Naturally acquired immunity to malaria develops only after years of repeated exposure to Plasmodium parasites. Despite the key role antibodies play in protection, the cellular processes underlying the slow acquisition of immunity remain unknown. Using mouse models, we show that severe malaria infection inhibits the es...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Ryg-Cornejo V,Ioannidis LJ,Ly A,Chiu CY,Tellier J,Hill DL,Preston SP,Pellegrini M,Yu D,Nutt SL,Kallies A,Hansen DS

    更新日期:2016-01-05 00:00:00

  • Colonic Lysine Homocysteinylation Induced by High-Fat Diet Suppresses DNA Damage Repair.

    abstract::Colorectal cancer (CRC) onset is profoundly affected by Western diet. Here, we report that high-fat (HF) diet-induced, organ-specific colonic lysine homocysteinylation (K-Hcy) increase might promote CRC onset by impeding DNA damage repair. HF chow induced elevated methionyl-tRNA synthetase (MARS) expression and K-Hcy ...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Wang D,Zhao R,Qu YY,Mei XY,Zhang X,Zhou Q,Li Y,Yang SB,Zuo ZG,Chen YM,Lin Y,Xu W,Chen C,Zhao SM,Zhao JY

    更新日期:2018-10-09 00:00:00

  • Linking Memories across Time via Neuronal and Dendritic Overlaps in Model Neurons with Active Dendrites.

    abstract::Memories are believed to be stored in distributed neuronal assemblies through activity-induced changes in synaptic and intrinsic properties. However, the specific mechanisms by which different memories become associated or linked remain a mystery. Here, we develop a simplified, biophysically inspired network model tha...

    journal_title:Cell reports

    pub_type: 杂志文章


    authors: Kastellakis G,Silva AJ,Poirazi P

    更新日期:2016-11-01 00:00:00