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Susan kaech

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https://www.readbyqxmd.com/read/28475890/metabolic-instruction-of-immunity
#1
REVIEW
Michael D Buck, Ryan T Sowell, Susan M Kaech, Erika L Pearce
Choices have consequences. Immune cells survey and migrate throughout the body and sometimes take residence in niche environments with distinct communities of cells, extracellular matrix, and nutrients that may differ from those in which they matured. Imbedded in immune cell physiology are metabolic pathways and metabolites that not only provide energy and substrates for growth and survival, but also instruct effector functions, differentiation, and gene expression. This review of immunometabolism will reference the most recent literature to cover the choices that environments impose on the metabolism and function of immune cells and highlight their consequences during homeostasis and disease...
May 4, 2017: Cell
https://www.readbyqxmd.com/read/28458087/reenergizing-t-cell-anti-tumor-immunity-by-harnessing-immunometabolic-checkpoints-and-machineries
#2
REVIEW
Ping-Chih Ho, Susan M Kaech
T cells patrol our bodies preventing pathogenic infections and malignant cell outgrowth. However, T cells must be properly controlled because aberrant or persistent T cell responses can damage tissues and contribute to autoimmune diseases and other chronic inflammatory diseases including metabolic syndrome. One regulatory mechanism utilized in immune cells is immunometabolic regulation, which ensures immune cells properly respond to systemic and peripheral metabolic cues. Recent work has suggested that deregulated metabolism in tumor cells creates a microenvironmental barrier for mounting effective anti-tumor immune responses...
April 27, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28410989/polycomb-repressive-complex-2-mediated-chromatin-repression-guides-effector-cd8-t-cell-terminal-differentiation-and-loss-of-multipotency
#3
Simon M Gray, Robert A Amezquita, Tianxia Guan, Steven H Kleinstein, Susan M Kaech
Understanding immunological memory formation depends on elucidating how multipotent memory precursor (MP) cells maintain developmental plasticity and longevity to provide long-term immunity while other effector cells develop into terminally differentiated effector (TE) cells with limited survival. Profiling active (H3K27ac) and repressed (H3K27me3) chromatin in naive, MP, and TE CD8(+) T cells during viral infection revealed increased H3K27me3 deposition at numerous pro-memory and pro-survival genes in TE relative to MP cells, indicative of fate restriction, but permissive chromatin at both pro-memory and pro-effector genes in MP cells, indicative of multipotency...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28379630/uv-induced-somatic-mutations-elicit-a-functional-t-cell-response-in-the-yummer1-7-mouse-melanoma-model
#4
Jake Wang, Curtis Jamison Perry, Katrina Meeth, Durga Thakral, William Damsky, Goran Micevic, Susan Kaech, Kim Blenman, Marcus Bosenberg
Human melanomas exhibit relatively high somatic mutation burden compared to other malignancies. These somatic mutations may produce neoantigens that are recognized by the immune system, leading to an anti-tumor response. By irradiating a parental mouse melanoma cell line carrying three driver mutations with UVB and expanding a single cell clone, we generated a mutagenized model that exhibits high somatic mutation burden. When inoculated at low cell numbers in immunocompetent C57BL/6J mice, YUMMER1.7 (YUMM Exposed to Radiation) regresses after a brief period of growth...
April 5, 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/28295222/traf3-cyld-mutations-identify-a-distinct-subset-of-human-papillomavirus-associated-head-and-neck-squamous-cell-carcinoma
#5
Michael Hajek, Andrew Sewell, Susan Kaech, Barbara Burtness, Wendell G Yarbrough, Natalia Issaeva
BACKGROUND: The incidence of human papillomavirus (HPV)-associated (HPV-positive) head and neck squamous cell carcinoma (HNSCC) of the oropharynx has dramatically increased over the last decade and continues to rise. Newly diagnosed HPV-positive HNSCCs in the United States currently outnumber any other HPV-associated cancers, including cervical cancer. Despite introduction of the HPV vaccine, the epidemic of HPV-positive HNSCC is expected to continue for approximately 60 years. Compared with patients who have tobacco-associated HNSCC, those who have HPV-positive HNSCC have better overall survival and response to treatment...
May 15, 2017: Cancer
https://www.readbyqxmd.com/read/28225757/immunology-the-chronicles-of-t-cell-exhaustion
#6
Robert A Amezquita, Susan M Kaech
No abstract text is available yet for this article.
February 22, 2017: Nature
https://www.readbyqxmd.com/read/27824591/nk-cell-responses-redefine-immunological-memory
#7
REVIEW
Nicholas M Adams, Timothy E O'Sullivan, Clair D Geary, Jenny M Karo, Robert A Amezquita, Nikhil S Joshi, Susan M Kaech, Joseph C Sun
Immunological memory has traditionally been regarded as a unique trait of the adaptive immune system. Nevertheless, there is evidence of immunological memory in lower organisms and invertebrates, which lack an adaptive immune system. Despite their innate ability to rapidly produce effector cytokines and kill virally infected or transformed cells, NK cells also exhibit adaptive characteristics such as clonal expansion, longevity, self-renewal, and robust recall responses to antigenic or nonantigenic stimuli...
October 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27617863/abc-transporters-and-nr4a1-identify-a-quiescent-subset-of-tissue-resident-memory-t-cells
#8
Chandra Sekhar Boddupalli, Shiny Nair, Simon M Gray, Heba N Nowyhed, Rakesh Verma, Joanna A Gibson, Clara Abraham, Deepak Narayan, Juan Vasquez, Catherine C Hedrick, Richard A Flavell, Kavita M Dhodapkar, Susan M Kaech, Madhav V Dhodapkar
Immune surveillance in tissues is mediated by a long-lived subset of tissue-resident memory T cells (Trm cells). A putative subset of tissue-resident long-lived stem cells is characterized by the ability to efflux Hoechst dyes and is referred to as side population (SP) cells. Here, we have characterized a subset of SP T cells (Tsp cells) that exhibit a quiescent (G0) phenotype in humans and mice. Human Trm cells in the gut and BM were enriched in Tsp cells that were predominantly in the G0 stage of the cell cycle...
October 3, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27610560/probing-the-diversity-of-t%C3%A2-cell-dysfunction-in-cancer
#9
COMMENT
Ryan T Sowell, Susan M Kaech
T cell dysfunction in cancer comes in many forms, with two new varieties reported in this issue. Daley et al. find that T cells expressing γδ T cell receptors (TCR) promote pancreatic tumor growth by inhibiting activation of T cells with conventional TCRs. Singer et al. characterize dysfunctional tumor infiltrating lymphocytes to reveal a role for zinc homeostasis in anti-tumor immunity.
September 8, 2016: Cell
https://www.readbyqxmd.com/read/27477778/il-2-in-the-tumor-microenvironment-is-necessary-for-wiskott-aldrich-syndrome-protein-deficient-nk-cells-to-respond-to-tumors-in-vivo
#10
Joanna S Kritikou, Carin I M Dahlberg, Marisa A P Baptista, Arnika K Wagner, Pinaki P Banerjee, Lavesh Amar Gwalani, Cecilia Poli, Sudeepta K Panda, Klas Kärre, Susan M Kaech, Fredrik Wermeling, John Andersson, Jordan S Orange, Hanna Brauner, Lisa S Westerberg
To kill target cells, natural killer (NK) cells organize signaling from activating and inhibitory receptors to form a lytic synapse. Wiskott-Aldrich syndrome (WAS) patients have loss-of-function mutations in the actin regulator WASp and suffer from immunodeficiency with increased risk to develop lymphoreticular malignancies. NK cells from WAS patients fail to form lytic synapses, however, the functional outcome in vivo remains unknown. Here, we show that WASp KO NK cells had decreased capacity to degranulate and produce IFNγ upon NKp46 stimulation and this was associated with reduced capacity to kill MHC class I-deficient hematopoietic grafts...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27385825/ccr7-expression-alters-memory-cd8-t-cell-homeostasis-by-regulating-occupancy-in-il-7-and-il-15-dependent-niches
#11
Yong Woo Jung, Hyun Gyung Kim, Curtis J Perry, Susan M Kaech
C-C receptor 7 (CCR7) is important to allow T cells and dendritic cells to migrate toward CCL19- and CCL21-producing cells in the T-cell zone of the spleen and lymph nodes. The role of this chemokine receptor in regulating the homeostasis of effector and memory T cells during acute viral infection is poorly defined, however. In this study, we show that CCR7 expression alters memory CD8 T-cell homeostasis following lymphocytic choriomeningitis virus infection. Greater numbers of CCR7-deficient memory T cells were formed and maintained compared with CCR7-sufficient memory T cells, especially in the lung and bone marrow...
July 19, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26994137/characterization-of-diabetogenic-cd8-t-cells-immune-therapy-with-metabolic-blockade
#12
COMMENT
Justin W Garyu, Mohamed Uduman, Alex Stewart, Jinxiu Rui, Songyan Deng, Jared Shenson, Matt M Staron, Susan M Kaech, Steven H Kleinstein, Kevan C Herold
Type 1 diabetes mellitus is caused by the killing of insulin-producing β cells by CD8+T cells. The disease progression, which is chronic, does not follow a course like responses to conventional antigens such as viruses, but accelerates as glucose tolerance deteriorates. To identify the unique features of the autoimmune effectors that may explain this behavior, we analyzed diabetogenic CD8+ T cells that recognize a peptide from the diabetes antigen IGRP (NRP-V7-reactive) in prediabetic NOD mice and compared them to others that shared their phenotype (CD44(+)CD62L(lo)PD-1(+)CXCR3(+)) but negative for diabetes antigen tetramers and to LCMV (lymphocytic choriomeningitis)-reactive CD8+ T cells...
May 20, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/26950239/a-molecular-threshold-for-effector-cd8-t-cell-differentiation-controlled-by-transcription-factors-blimp-1-and-t-bet
#13
Annie Xin, Frederick Masson, Yang Liao, Simon Preston, Tianxia Guan, Renee Gloury, Moshe Olshansky, Jian-Xin Lin, Peng Li, Terence P Speed, Gordon K Smyth, Matthias Ernst, Warren J Leonard, Marc Pellegrini, Susan M Kaech, Stephen L Nutt, Wei Shi, Gabrielle T Belz, Axel Kallies
T cell responses are guided by cytokines that induce transcriptional regulators, which ultimately control differentiation of effector and memory T cells. However, it is unknown how the activities of these molecular regulators are coordinated and integrated during the differentiation process. Using genetic approaches and transcriptional profiling of antigen-specific CD8(+) T cells, we reveal a common program of effector differentiation that is regulated by IL-2 and IL-12 signaling and the combined activities of the transcriptional regulators Blimp-1 and T-bet...
April 2016: Nature Immunology
https://www.readbyqxmd.com/read/26781939/the-multifaceted-role-of-cd4-t-cells-in-cd8-t-cell-memory
#14
REVIEW
Brian J Laidlaw, Joseph E Craft, Susan M Kaech
Following infection, T cells differentiate into a heterogeneous population of effector T cells that can mediate pathogen clearance. A subset of these effector T cells possesses the ability to survive long term and mature into memory T cells that can provide long-term immunity. Understanding the signals that regulate the development of memory T cells is crucial to efforts to design vaccines capable of eliciting T cell-based immunity. CD4(+) T cells are essential in the formation of protective memory CD8(+) T cells following infection or immunization...
February 2016: Nature Reviews. Immunology
https://www.readbyqxmd.com/read/26503446/the-transcription-factors-zeb2-and-t-bet-cooperate-to-program-cytotoxic-t-cell-terminal-differentiation-in-response-to-lcmv-viral-infection
#15
Claudia X Dominguez, Robert A Amezquita, Tianxia Guan, Heather D Marshall, Nikhil S Joshi, Steven H Kleinstein, Susan M Kaech
The transcription factor T-bet is critical for cytotoxic T lymphocyte (CTL) differentiation, but it is unclear how it operates in a graded manner in the formation of both terminal effector and memory precursor cells during viral infection. We find that, at high concentrations, T-bet induced expression of Zeb2 mRNA, which then triggered CTLs to adopt terminally differentiated states. ZEB2 and T-bet cooperate to switch on a terminal CTL differentiation program, while simultaneously repressing genes necessary for central memory CTL development...
November 16, 2015: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/26410627/the-interleukin-2-mtorc1-kinase-axis-defines-the-signaling-differentiation-and-metabolism-of-t-helper-1-and-follicular-b-helper-t-cells
#16
John P Ray, Matthew M Staron, Justin A Shyer, Ping-Chih Ho, Heather D Marshall, Simon M Gray, Brian J Laidlaw, Koichi Araki, Rafi Ahmed, Susan M Kaech, Joe Craft
The differentiation of CD4(+) helper T cell subsets with diverse effector functions is accompanied by changes in metabolism required to meet their bioenergetic demands. We find that follicular B helper T (Tfh) cells exhibited less proliferation, glycolysis, and mitochondrial respiration, accompanied by reduced mTOR kinase activity compared to T helper 1 (Th1) cells in response to acute viral infection. IL-2-mediated activation of the Akt kinase and mTORc1 signaling was both necessary and sufficient to shift differentiation away from Tfh cells, instead promoting that of Th1 cells...
October 20, 2015: Immunity
https://www.readbyqxmd.com/read/26321681/phosphoenolpyruvate-is-a-metabolic-checkpoint-of-anti-tumor-t-cell-responses
#17
Ping-Chih Ho, Jessica Dauz Bihuniak, Andrew N Macintyre, Matthew Staron, Xiaojing Liu, Robert Amezquita, Yao-Chen Tsui, Guoliang Cui, Goran Micevic, Jose C Perales, Steven H Kleinstein, E Dale Abel, Karl L Insogna, Stefan Feske, Jason W Locasale, Marcus W Bosenberg, Jeffrey C Rathmell, Susan M Kaech
Activated T cells engage aerobic glycolysis and anabolic metabolism for growth, proliferation, and effector functions. We propose that a glucose-poor tumor microenvironment limits aerobic glycolysis in tumor-infiltrating T cells, which suppresses tumoricidal effector functions. We discovered a new role for the glycolytic metabolite phosphoenolpyruvate (PEP) in sustaining T cell receptor-mediated Ca(2+)-NFAT signaling and effector functions by repressing sarco/ER Ca(2+)-ATPase (SERCA) activity. Tumor-specific CD4 and CD8 T cells could be metabolically reprogrammed by increasing PEP production through overexpression of phosphoenolpyruvate carboxykinase 1 (PCK1), which bolstered effector functions...
September 10, 2015: Cell
https://www.readbyqxmd.com/read/26147684/production-of-il-10-by-cd4-regulatory-t-cells-during-the-resolution-of-infection-promotes-the-maturation-of-memory-cd8-t-cells
#18
Brian J Laidlaw, Weiguo Cui, Robert A Amezquita, Simon M Gray, Tianxia Guan, Yisi Lu, Yasushi Kobayashi, Richard A Flavell, Steven H Kleinstein, Joe Craft, Susan M Kaech
Memory CD8(+) T cells are critical for host defense upon reexposure to intracellular pathogens. We found that interleukin 10 (IL-10) derived from CD4(+) regulatory T cells (Treg cells) was necessary for the maturation of memory CD8(+) T cells following acute infection with lymphocytic choriomeningitis virus (LCMV). Treg cell-derived IL-10 was most important during the resolution phase, calming inflammation and the activation state of dendritic cells. Adoptive transfer of IL-10-sufficient Treg cells during the resolution phase 'restored' the maturation of memory CD8(+) T cells in IL-10-deficient mice...
August 2015: Nature Immunology
https://www.readbyqxmd.com/read/25957683/il-7-induced-glycerol-transport-and-tag-synthesis-promotes-memory-cd8-t-cell-longevity
#19
Guoliang Cui, Matthew M Staron, Simon M Gray, Ping-Chih Ho, Robert A Amezquita, Jingxia Wu, Susan M Kaech
Memory T cells are critical for long-term immunity against reinfection and require interleukin-7 (IL-7), but the mechanisms by which IL-7 controls memory T cell survival, particularly metabolic fitness, remain elusive. We discover that IL-7 induces expression of the glycerol channel aquaporin 9 (AQP9) in virus-specific memory CD8+ T cells, but not naive cells, and that AQP9 is vitally required for their long-term survival. AQP9 deficiency impairs glycerol import into memory CD8+ T cells for fatty acid esterification and triglyceride (TAG) synthesis and storage...
May 7, 2015: Cell
https://www.readbyqxmd.com/read/25799228/prostaglandin-e2-and-programmed-cell-death-1-signaling-coordinately-impair-ctl-function-and-survival-during-chronic-viral-infection
#20
Jonathan H Chen, Curtis J Perry, Yao-Chen Tsui, Matthew M Staron, Ian A Parish, Claudia X Dominguez, Daniel W Rosenberg, Susan M Kaech
More than 10% of the world's population is chronically infected with HIV, hepatitis C virus (HCV) or hepatitis B virus (HBV), all of which can cause severe disease and death. These viruses persist in part because continuous antigenic stimulation causes the deterioration of virus-specific cytotoxic T lymphocyte (CTL) function and survival. Additionally, antiviral CTLs autonomously suppress their responses to limit immunopathology by upregulating inhibitory receptors such as programmed cell death 1 (PD-1). Identification and blockade of the pathways that induce CTL dysfunction may facilitate the clearance of chronic viral infections...
April 2015: Nature Medicine
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