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Susan kaech

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https://www.readbyqxmd.com/read/29212666/stat4-and-t-bet-control-follicular-helper-t-cell-development-in-viral-infections
#1
Jason S Weinstein, Brian J Laidlaw, Yisi Lu, Jessica K Wang, Vincent P Schulz, Ningcheng Li, Edward I Herman, Susan M Kaech, Patrick G Gallagher, Joe Craft
Follicular helper T (Tfh) cells promote germinal center (GC) B cell survival and proliferation and guide their differentiation and immunoglobulin isotype switching by delivering contact-dependent and soluble factors, including IL-21, IL-4, IL-9, and IFN-γ. IL-21 and IFN-γ are coexpressed by Tfh cells during viral infections, but transcriptional regulation of these cytokines is not completely understood. In this study, we show that the T helper type 1 cell (Th1 cell) transcriptional regulators T-bet and STAT4 are coexpressed with Bcl6 in Tfh cells after acute viral infection, with a temporal decline in T-bet in the waning response...
December 6, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29054998/interleukin-10-from-cd4-follicular-regulatory-t-cells-promotes-the-germinal-center-response
#2
Brian J Laidlaw, Yisi Lu, Robert A Amezquita, Jason S Weinstein, Jason A Vander Heiden, Namita T Gupta, Steven H Kleinstein, Susan M Kaech, Joe Craft
CD4(+) follicular regulatory T (Tfr) cells suppress B cell responses through modulation of follicular helper T (Tfh) cells and germinal center (GC) development. We found that Tfr cells can also promote the GC response through provision of interleukin-10 (IL-10) after acute infection with lymphocytic choriomeningitis virus (LCMV). Sensing of IL-10 by B cells was necessary for optimal development of the GC response. GC B cells formed in the absence of Treg cell-derived IL-10 displayed an altered dark zone state and decreased expression of the transcription factor Forkhead box protein 1 (FOXO1)...
October 20, 2017: Science Immunology
https://www.readbyqxmd.com/read/29025772/impaired-hla-class-i-antigen-processing-and-presentation-as-a-mechanism-of-acquired-resistance-to-immune-checkpoint-inhibitors-in-lung-cancer
#3
Scott Gettinger, Jungmin Choi, Katherine Hastings, Anna Truini, Ila Datar, Ryan Sowell, Anna Wurtz, Weilai Dong, Guoping Cai, Mary Ann Melnick, Victor Y Du, Joseph Schlessinger, Sarah B Goldberg, Anne Chiang, Miguel F Sanmamed, Ignacio Melero, Jackeline Agorreta, Luis M Montuenga, Richard Lifton, Soldano Ferrone, Paula Kavathas, David L Rimm, Susan M Kaech, Kurt A Schalper, Roy S Herbst, Katerina Politi
Mechanisms of acquired resistance to immune checkpoint inhibitors (ICIs) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell surface HLA class I expression in the tumor and a matched patient-derived xenograft (PDX)...
October 12, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28894184/il-7-plays-a-critical-role-for-the-homeostasis-of-allergen-specific-memory-cd4-t-cells-in-the-lung-and-airways
#4
Seung-Min Yeon, Lea Halim, Anmol Chandele, Curtis J Perry, Sang Hoon Kim, Sun-Uk Kim, Youngjoo Byun, Soon Hong Yuk, Susan M Kaech, Yong Woo Jung
Memory T cells respond rapidly to repeated antigen exposure and can maintain their population for extended periods through self-renewal. These characteristics of memory T cells have mainly been studied during viral infections, whereas their existence and functions in allergic diseases have been studied incompletely. Since allergic patients can suffer repeated relapses caused by intermittent allergen exposure, we hypothesized that allergen- specific memory Th2 cells are present and the factors necessary for the maintenance of these cells are provided by the lung and airways...
September 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28827827/transient-expression-of-zbtb32-in-anti-viral-cd8-t-cells-limits-the-magnitude-of-the-effector-response-and-the-generation-of-memory
#5
Hyun Mu Shin, Varun N Kapoor, Gwanghun Kim, Peng Li, Hang-Rae Kim, M Suresh, Susan M Kaech, E John Wherry, Liisa K Selin, Warren J Leonard, Raymond M Welsh, Leslie J Berg
Virus infections induce CD8+ T cell responses comprised of a large population of terminal effector cells and a smaller subset of long-lived memory cells. The transcription factors regulating the relative expansion versus the long-term survival potential of anti-viral CD8+ T cells are not completely understood. We identified ZBTB32 as a transcription factor that is transiently expressed in effector CD8+ T cells. After acute virus infection, CD8+ T cells deficient in ZBTB32 showed enhanced virus-specific CD8+ T cell responses, and generated increased numbers of virus-specific memory cells; in contrast, persistent expression of ZBTB32 suppressed memory cell formation...
August 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28713870/il-10-induces-a-stat3-dependent-autoregulatory-loop-in-th2-cells-that-promotes-blimp-1-restriction-of-cell-expansion-via-antagonism-of-stat5-target-genes
#6
Amanda C Poholek, Dragana Jankovic, Alejandro V Villarino, Franziska Petermann, Angela Hettinga, Dror S Shouval, Scott B Snapper, Susan M Kaech, Stephen R Brooks, Golnaz Vahedi, Alan Sher, Yuka Kanno, John J O'Shea
Blimp-1 expression in T cells extinguishes the fate of T follicular helper cells, drives terminal differentiation, and limits autoimmunity. Although various factors have been described to control Blimp-1 expression in T cells, little is known about what regulates Blimp-1 expression in T helper 2 (TH2) cells and the molecular basis of its actions. We report that signal transducer and activator of transcription 3 (STAT3) unexpectedly played a critical role in regulating Blimp-1 in TH2 cells. Furthermore, we found that the cytokine interleukin-10 (IL-10) acted directly on TH2 cells and was necessary and sufficient to induce optimal Blimp-1 expression through STAT3...
October 2016: Science Immunology
https://www.readbyqxmd.com/read/28701508/prdm1-regulates-thymic-epithelial-function-to-prevent-autoimmunity
#7
Natalie A Roberts, Brian D Adams, Nicholas I McCarthy, Reuben M Tooze, Sonia M Parnell, Graham Anderson, Susan M Kaech, Valerie Horsley
Autoimmunity is largely prevented by medullary thymic epithelial cells (TECs) through their expression and presentation of tissue-specific Ags to developing thymocytes, resulting in deletion of self-reactive T cells and supporting regulatory T cell development. The transcription factor Prdm1 has been implicated in autoimmune diseases in humans through genome-wide association studies and in mice using cell type-specific deletion of Prdm1 in T and dendritic cells. In this article, we demonstrate that Prdm1 functions in TECs to prevent autoimmunity in mice...
August 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28475890/metabolic-instruction-of-immunity
#8
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
#9
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...
June 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
#10
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
#11
Jake Wang, Curtis J 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 antitumor 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 (Yale University Mouse Melanoma Exposed to Radiation) regresses after a brief period of growth...
July 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
#12
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
#13
COMMENT
Robert A Amezquita, Susan M Kaech
No abstract text is available yet for this article.
March 9, 2017: Nature
https://www.readbyqxmd.com/read/27824591/nk-cell-responses-redefine-immunological-memory
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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