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https://www.readbyqxmd.com/read/29320737/genomic-circuitry-underlying-immunological-response-to-pediatric-acute-respiratory-infection
#1
Sarah E Henrickson, Sasikanth Manne, Douglas V Dolfi, Kathleen D Mansfield, Kaela Parkhouse, Rakesh D Mistry, Elizabeth R Alpern, Scott E Hensley, Kathleen E Sullivan, Susan E Coffin, E John Wherry
Acute respiratory tract viral infections (ARTIs) cause significant morbidity and mortality. CD8 T cells are fundamental to host responses, but transcriptional alterations underlying anti-viral mechanisms and links to clinical characteristics remain unclear. CD8 T cell transcriptional circuitry in acutely ill pediatric patients with influenza-like illness was distinct for different viral pathogens. Although changes included expected upregulation of interferon-stimulated genes (ISGs), transcriptional downregulation was prominent upon exposure to innate immune signals in early IFV infection...
January 9, 2018: Cell Reports
https://www.readbyqxmd.com/read/29150566/the-loss-of-tet2-promotes-cd8-t-cell-memory-differentiation
#2
Shannon A Carty, Mercy Gohil, Lauren B Banks, Renee M Cotton, Matthew E Johnson, Erietta Stelekati, Andrew D Wells, E John Wherry, Gary A Koretzky, Martha S Jordan
T cell differentiation requires appropriate regulation of DNA methylation. In this article, we demonstrate that the methylcytosine dioxygenase ten-eleven translocation (TET)2 regulates CD8(+) T cell differentiation. In a murine model of acute viral infection, TET2 loss promotes early acquisition of a memory CD8(+) T cell fate in a cell-intrinsic manner without disrupting Ag-driven cell expansion or effector function. Upon secondary recall, TET2-deficient memory CD8(+) T cells demonstrate superior pathogen control...
November 17, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29137933/cd4-t-cell-differentiation-in-chronic-viral-infections-the-tfh-perspective
#3
REVIEW
Laura A Vella, Ramin S Herati, E John Wherry
CD4(+) T cells play a critical role in the response to chronic viral infections during the acute phase and in the partial containment of infections once chronic infection is established. As infection persists, the virus-specific CD4(+) T cell response begins to shift in phenotype. The predominant change described in both mouse and human studies of chronic viral infection is a decrease in detectable T helper type (Th)1 responses. Some Th1 loss is due to decreased proliferative potential and decreased cytokine production in the setting of chronic antigen exposure...
November 11, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/29031786/differentiation-and-protective-capacity-of-virus-specific-cd8-t-cells-suggest-murine-norovirus-persistence-in-an-immune-privileged-enteric-niche
#4
Vesselin T Tomov, Olesya Palko, Chi Wai Lau, Ajinkya Pattekar, Yuhang Sun, Ralitza Tacheva, Bertram Bengsch, Sasikanth Manne, Gabriela L Cosma, Laurence C Eisenlohr, Timothy J Nice, Herbert W Virgin, E John Wherry
Noroviruses can establish chronic infections with active viral shedding in healthy humans but whether persistence is associated with adaptive immune dysfunction is unknown. We used genetically engineered strains of mouse norovirus (MNV) to investigate CD8(+) T cell differentiation during chronic infection. We found that chronic infection drove MNV-specific tissue-resident memory (Trm) CD8(+) T cells to a differentiation state resembling inflationary effector responses against latent cytomegalovirus with only limited evidence of exhaustion...
October 17, 2017: Immunity
https://www.readbyqxmd.com/read/28930659/group-1-innate-lymphoid-cell-lineage-identity-is-determined-by-a-cis-regulatory-element-marked-by-a-long-non-coding-rna
#5
Walter K Mowel, Sam J McCright, Jonathan J Kotzin, Magalie A Collet, Asli Uyar, Xin Chen, Alexandra DeLaney, Sean P Spencer, Anthony T Virtue, EnJun Yang, Alejandro Villarino, Makoto Kurachi, Margaret C Dunagin, Gretchen Harms Pritchard, Judith Stein, Cynthia Hughes, Diogo Fonseca-Pereira, Henrique Veiga-Fernandes, Arjun Raj, Taku Kambayashi, Igor E Brodsky, John J O'Shea, E John Wherry, Loyal A Goff, John L Rinn, Adam Williams, Richard A Flavell, Jorge Henao-Mejia
Commitment to the innate lymphoid cell (ILC) lineage is determined by Id2, a transcriptional regulator that antagonizes T and B cell-specific gene expression programs. Yet how Id2 expression is regulated in each ILC subset remains poorly understood. We identified a cis-regulatory element demarcated by a long non-coding RNA (lncRNA) that controls the function and lineage identity of group 1 ILCs, while being dispensable for early ILC development and homeostasis of ILC2s and ILC3s. The locus encoding this lncRNA, which we termed Rroid, directly interacted with the promoter of its neighboring gene, Id2, in group 1 ILCs...
September 19, 2017: Immunity
https://www.readbyqxmd.com/read/28903040/mir-150-regulates-memory-cd8%C3%A2-t-cell-differentiation-via-c-myb
#6
Zeyu Chen, Erietta Stelekati, Makoto Kurachi, Sixiang Yu, Zhangying Cai, Sasikanth Manne, Omar Khan, Xiaolu Yang, E John Wherry
MicroRNAs play an important role in T cell responses. However, how microRNAs regulate CD8 T cell memory remains poorly defined. Here, we found that miR-150 negatively regulates CD8 T cell memory in vivo. Genetic deletion of miR-150 disrupted the balance between memory precursor and terminal effector CD8 T cells following acute viral infection. Moreover, miR-150-deficient memory CD8 T cells were more protective upon rechallenge. A key circuit whereby miR-150 repressed memory CD8 T cell development through the transcription factor c-Myb was identified...
September 12, 2017: Cell Reports
https://www.readbyqxmd.com/read/28858287/optimized-retroviral-transduction-of-mouse-t-cells-for-in-vivo-assessment-of-gene-function
#7
Makoto Kurachi, Junko Kurachi, Zeyu Chen, John Johnson, Omar Khan, Bertram Bengsch, Erietta Stelekati, John Attanasio, Laura M McLane, Michio Tomura, Satoshi Ueha, E John Wherry
Retroviral (RV) expression of genes of interest (GOIs) is an invaluable tool and has formed the foundation of cellular engineering for adoptive cell therapy in cancer and other diseases. However, monitoring of transduced T cells long term (weeks to months) in vivo remains challenging because of the low frequency and often poor durability of transduced T cells over time when transferred without enrichment. Traditional methods often require additional overnight in vitro culture after transduction. Moreover, in vitro-generated effector CD8(+) T cells enriched by sorting often have reduced viability, making it difficult to monitor the fate of transferred cells in vivo...
September 2017: Nature Protocols
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
#8
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/28620653/successive-annual-influenza-vaccination-induces-a-recurrent-oligoclonotypic-memory-response-in-circulating-t-follicular-helper-cells
#9
Ramin Sedaghat Herati, Alexander Muselman, Laura Vella, Bertram Bengsch, Kaela Parkhouse, Daniel Del Alcazar, Jonathan Kotzin, Susan A Doyle, Pablo Tebas, Scott E Hensley, Laura F Su, Kenneth E Schmader, E John Wherry
T follicular helper (Tfh) CD4 cells are crucial providers of B cell help during adaptive immune responses. A circulating population of CD4 T cells, termed cTfh, have similarity to lymphoid Tfh, can provide B cell help, and responded to influenza vaccination. However, it is unclear whether human vaccination-induced cTfh respond in an antigen-specific manner and whether they form long-lasting memory. Here, we identified a cTfh population that expressed multiple T cell activation markers and could be readily identified by coexpression of ICOS and CD38...
February 2017: Science Immunology
https://www.readbyqxmd.com/read/28397821/t-cell-invigoration-to-tumour-burden-ratio-associated-with-anti-pd-1-response
#10
Alexander C Huang, Michael A Postow, Robert J Orlowski, Rosemarie Mick, Bertram Bengsch, Sasikanth Manne, Wei Xu, Shannon Harmon, Josephine R Giles, Brandon Wenz, Matthew Adamow, Deborah Kuk, Katherine S Panageas, Cristina Carrera, Phillip Wong, Felix Quagliarello, Bradley Wubbenhorst, Kurt D'Andrea, Kristen E Pauken, Ramin S Herati, Ryan P Staupe, Jason M Schenkel, Suzanne McGettigan, Shawn Kothari, Sangeeth M George, Robert H Vonderheide, Ravi K Amaravadi, Giorgos C Karakousis, Lynn M Schuchter, Xiaowei Xu, Katherine L Nathanson, Jedd D Wolchok, Tara C Gangadhar, E John Wherry
Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells)...
May 4, 2017: Nature
https://www.readbyqxmd.com/read/28348037/what-is-the-predictive-value-of-animal-models-for-vaccine-efficacy-in-humans-consideration-of-strategies-to-improve-the-value-of-animal-models
#11
Ramin Sedaghat Herati, E John Wherry
Animal models are an essential feature of the vaccine design toolkit. Although animal models have been invaluable in delineating the mechanisms of immune function, their precision in predicting how well specific vaccines work in humans is often suboptimal. There are, of course, many obvious species differences that may limit animal models from predicting all details of how a vaccine works in humans. However, careful consideration of which animal models may have limitations should also allow more accurate interpretations of animal model data and more accurate predictions of what is to be expected in clinical trials...
March 27, 2017: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/28322863/deep-immune-profiling-by-mass-cytometry-links-human-t-and-nk-cell-differentiation-and-cytotoxic-molecule-expression-patterns
#12
Bertram Bengsch, Takuya Ohtani, Ramin Sedaghat Herati, Niels Bovenschen, Kyong-Mi Chang, E John Wherry
The elimination of infected or tumor cells by direct lysis is a key T and NK cell effector function. T and NK cells can kill target cells by coordinated secretion of cytotoxic granules containing one or both pore-forming proteins, perforin and granulysin and combinations of granzyme (Gzm) family effector proteases (in humans: Gzm A, B, K, M and H). Understanding the pattern of expression of cytotoxic molecules and the relationship to different states of T and NK cells may have direct relevance for immune responses in autoimmunity, infectious disease and cancer...
March 19, 2017: Journal of Immunological Methods
https://www.readbyqxmd.com/read/28212439/correction-type-i-interferon-receptor-deficiency-in-dendritic-cells-facilitates-systemic-murine-norovirus-persistence-despite-enhanced-adaptive-immunity
#13
Timothy J Nice, Lisa C Osborne, Vesselin T Tomov, David Artis, E John Wherry, Herbert W Virgin
[This corrects the article DOI: 10.1371/journal.ppat.1005684.].
February 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/27912061/tumor-interferon-signaling-regulates-a-multigenic-resistance-program-to-immune-checkpoint-blockade
#14
Joseph L Benci, Bihui Xu, Yu Qiu, Tony J Wu, Hannah Dada, Christina Twyman-Saint Victor, Lisa Cucolo, David S M Lee, Kristen E Pauken, Alexander C Huang, Tara C Gangadhar, Ravi K Amaravadi, Lynn M Schuchter, Michael D Feldman, Hemant Ishwaran, Robert H Vonderheide, Amit Maity, E John Wherry, Andy J Minn
Therapeutic blocking of the PD1 pathway results in significant tumor responses, but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB) and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27810945/pregnancy-promotes-tolerance-to-future-offspring-by-programming-selective-dysfunction-in-long-lived-maternal-t-cells
#15
Brendan M Barton, Rong Xu, E John Wherry, Paige M Porrett
Fetal antigen available during pregnancy induces the proliferation of maternal T cells. It is unknown, however, whether these antigen-activated T cells differentiate into long-lived memory T cells that are capable of mediating rapid-recall responses to tissue antigens. To test the hypothesis that pregnancy induces an alternative fate in fetal-specific maternal T cells, we used a murine model to track longitudinally fetal-specific T cells in pregnant and postpartum animals and test the response of these cells when challenged with the same antigen during sequential pregnancy or skin transplantation...
April 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/27789799/the-epigenetic-landscape-of-t-cell-exhaustion
#16
Debattama R Sen, James Kaminski, R Anthony Barnitz, Makoto Kurachi, Ulrike Gerdemann, Kathleen B Yates, Hsiao-Wei Tsao, Jernej Godec, Martin W LaFleur, Flavian D Brown, Pierre Tonnerre, Raymond T Chung, Damien C Tully, Todd M Allen, Nicole Frahm, Georg M Lauer, E John Wherry, Nir Yosef, W Nicholas Haining
Exhausted T cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (PD-1). However, the regulation of gene expression in exhausted T cells is poorly understood. Here, we define the accessible chromatin landscape in exhausted CD8(+) T cells and show that it is distinct from functional memory CD8(+) T cells. Exhausted CD8(+) T cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers...
December 2, 2016: Science
https://www.readbyqxmd.com/read/27789795/epigenetic-stability-of-exhausted-t-cells-limits-durability-of-reinvigoration-by-pd-1-blockade
#17
Kristen E Pauken, Morgan A Sammons, Pamela M Odorizzi, Sasikanth Manne, Jernej Godec, Omar Khan, Adam M Drake, Zeyu Chen, Debattama R Sen, Makoto Kurachi, R Anthony Barnitz, Caroline Bartman, Bertram Bengsch, Alexander C Huang, Jason M Schenkel, Golnaz Vahedi, W Nicholas Haining, Shelley L Berger, E John Wherry
Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEX into durable memory T cells (TMEM) is unclear. We found that reinvigoration of TEX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated TEX became reexhausted if antigen concentration remained high and failed to become TMEM upon antigen clearance. TEX acquired an epigenetic profile distinct from that of effector T cells (TEFF) and TMEM cells that was minimally remodeled after PD-L1 blockade...
December 2, 2016: Science
https://www.readbyqxmd.com/read/27681619/antigen-exposure-shapes-the-ratio-between-antigen-specific-tregs-and-conventional-t-cells-in-human-peripheral-blood
#18
Laura F Su, Daniel Del Alcazar, Erietta Stelekati, E John Wherry, Mark M Davis
The T-cell receptor (TCR) is required for maturation and function of regulatory T cells (Tregs), but the ligand specificities of Tregs outside the context of transgenic TCRs are largely unknown. Using peptide-MHC tetramers, we isolated rare specific Foxp3(+) cells directly ex vivo from adult peripheral blood and defined their frequency and phenotype. We find that a proportion of circulating Tregs recognize foreign antigens and the frequency of these cells are similar to that of self-reactive Tregs in the absence of cognate infection...
October 11, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27525555/the-long-non-coding-rna-morrbid-regulates-bim-and-short-lived-myeloid-cell-lifespan
#19
Jonathan J Kotzin, Sean P Spencer, Sam J McCright, Dinesh B Uthaya Kumar, Magalie A Collet, Walter K Mowel, Ellen N Elliott, Asli Uyar, Michelle A Makiya, Margaret C Dunagin, Christian C D Harman, Anthony T Virtue, Stella Zhu, Will Bailis, Judith Stein, Cynthia Hughes, Arjun Raj, E John Wherry, Loyal A Goff, Amy D Klion, John L Rinn, Adam Williams, Richard A Flavell, Jorge Henao-Mejia
Neutrophils, eosinophils and 'classical' monocytes collectively account for about 70% of human blood leukocytes and are among the shortest-lived cells in the body. Precise regulation of the lifespan of these myeloid cells is critical to maintain protective immune responses and minimize the deleterious consequences of prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely unknown. Here we identify a long non-coding RNA that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and classical monocytes in response to pro-survival cytokines in mice...
September 8, 2016: Nature
https://www.readbyqxmd.com/read/27496729/bioenergetic-insufficiencies-due-to-metabolic-alterations-regulated-by-the-inhibitory-receptor-pd-1-are-an-early-driver-of-cd8-t-cell-exhaustion
#20
Bertram Bengsch, Andy L Johnson, Makoto Kurachi, Pamela M Odorizzi, Kristen E Pauken, John Attanasio, Erietta Stelekati, Laura M McLane, Michael A Paley, Greg M Delgoffe, E John Wherry
Dynamic reprogramming of metabolism is essential for T cell effector function and memory formation. However, the regulation of metabolism in exhausted CD8(+) T (Tex) cells is poorly understood. We found that during the first week of chronic lymphocytic choriomeningitis virus (LCMV) infection, before severe dysfunction develops, virus-specific CD8(+) T cells were already unable to match the bioenergetics of effector T cells generated during acute infection. Suppression of T cell bioenergetics involved restricted glucose uptake and use, despite persisting mechanistic target of rapamycin (mTOR) signaling and upregulation of many anabolic pathways...
August 16, 2016: Immunity
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