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Susan kaech

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
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
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
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
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
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
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
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
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
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
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
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
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
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
Rachel J Perry, João-Paulo G Camporez, Romy Kursawe, Paul M Titchenell, Dongyan Zhang, Curtis J Perry, Michael J Jurczak, Abulizi Abudukadier, Myoung Sook Han, Xian-Man Zhang, Hai-Bin Ruan, Xiaoyong Yang, Sonia Caprio, Susan M Kaech, Hei Sook Sul, Morris J Birnbaum, Roger J Davis, Gary W Cline, Kitt Falk Petersen, Gerald I Shulman
Impaired insulin-mediated suppression of hepatic glucose production (HGP) plays a major role in the pathogenesis of type 2 diabetes (T2D), yet the molecular mechanism by which this occurs remains unknown. Using a novel in vivo metabolomics approach, we show that the major mechanism by which insulin suppresses HGP is through reductions in hepatic acetyl CoA by suppression of lipolysis in white adipose tissue (WAT) leading to reductions in pyruvate carboxylase flux. This mechanism was confirmed in mice and rats with genetic ablation of insulin signaling and mice lacking adipose triglyceride lipase...
February 12, 2015: Cell
A Phillip West, William Khoury-Hanold, Matthew Staron, Michal C Tal, Cristiana M Pineda, Sabine M Lang, Megan Bestwick, Brett A Duguay, Nuno Raimundo, Donna A MacDuff, Susan M Kaech, James R Smiley, Robert E Means, Akiko Iwasaki, Gerald S Shadel
Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined...
April 23, 2015: Nature
Yinghong Hu, Young-Tae Lee, Susan M Kaech, Beth Garvy, Linda S Cauley
Tissue-resident memory CD8 T cells are a unique subset of virus-specific CTLs that bolster local immune responses after becoming lodged in previously infected tissues. These cells provide enhanced protection by intercepting returning pathogens before a new infection gets established. In contrast, central memory CD8 T cells circulate in the bloodstream and proliferate in secondary lymphoid organs before replenishing effector and memory CD8 T cell populations in remote parts of the body. Both populations of virus-specific memory CD8 T cells participate in immunity to influenza virus infection; however, the signaling pathways that instruct developing memory CD8 T cells to distribute to specific tissues are poorly defined...
March 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Juilee Thakar, Subhasis Mohanty, A Phillip West, Samit R Joshi, Ikuyo Ueda, Jean Wilson, Hailong Meng, Tamara P Blevins, Sui Tsang, Mark Trentalange, Barbara Siconolfi, Koonam Park, Thomas M Gill, Robert B Belshe, Susan M Kaech, Gerald S Shadel, Steven H Kleinstein, Albert C Shaw
To elucidate gene expression pathways underlying age-associated impairment in influenza vaccine response, we screened young (age 21-30) and older (age≥65) adults receiving influenza vaccine in two consecutive seasons and identified those with strong or absent response to vaccine, including a subset of older adults meeting criteria for frailty. PBMCs obtained prior to vaccination (Day 0) and at day 2 or 4, day 7 and day 28 post-vaccine were subjected to gene expression microarray analysis. We defined a response signature and also detected induction of a type I interferon response at day 2 and a plasma cell signature at day 7 post-vaccine in young responders...
January 2015: Aging
Heather D Marshall, John P Ray, Brian J Laidlaw, Nianzhi Zhang, Dipika Gawande, Matthew M Staron, Joe Craft, Susan M Kaech
T follicular helper cells (Tfh) are crucial for the initiation and maintenance of germinal center (GC) reactions and high affinity, isotype-switched antibody responses. In this study, we demonstrate that direct TGF-β signaling to CD4 T cells is important for the formation of influenza-specific Tfh cells, GC reactions, and development of isotype-switched, flu-specific antibody responses. Early during infection, TGF-β signaling suppressed the expression of the high affinity IL-2 receptor α chain (CD25) on virus-specific CD4 T cells, which tempered IL-2 signaling and STAT5 and mammalian target of rapamycin (mTOR) activation in Tfh precursor CD4 T cells...
2015: ELife
Matthew M Staron, Simon M Gray, Heather D Marshall, Ian A Parish, Jonathan H Chen, Curtis J Perry, Guoliang Cui, Ming O Li, Susan M Kaech
Protein kinase B (also known as AKT) and the mechanistic target of rapamycin (mTOR) are central regulators of T cell differentiation, proliferation, metabolism, and survival. Here, we show that during chronic murine lymphocytic choriomeningitis virus infection, activation of AKT and mTOR are impaired in antiviral cytotoxic T lymphocytes (CTLs), resulting in enhanced activity of the transcription factor FoxO1. Blockade of inhibitory receptor programmed cell death protein 1 (PD-1) in vivo increased mTOR activity in virus-specific CTLs, and its therapeutic effects were abrogated by the mTOR inhibitor rapamycin...
November 20, 2014: Immunity
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