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John wherry

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
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 ~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 while minimizing the deleterious consequences of prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely unknown. Here we identify a novel long non-coding RNA (lncRNA) that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and 'classical' monocytes in response to pro-survival cytokines...
August 15, 2016: Nature
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
Burton E Barnett, Ryan P Staupe, Pamela M Odorizzi, Olesya Palko, Vesselin T Tomov, Alison E Mahan, Bronwyn Gunn, Diana Chen, Michael A Paley, Galit Alter, Steven L Reiner, Georg M Lauer, John R Teijaro, E John Wherry
The role of Ab and B cells in preventing infection is established. In contrast, the role of B cell responses in containing chronic infections remains poorly understood. IgG2a (IgG1 in humans) can prevent acute infections, and T-bet promotes IgG2a isotype switching. However, whether IgG2a and B cell-expressed T-bet influence the host-pathogen balance during persisting infections is unclear. We demonstrate that B cell-specific loss of T-bet prevents control of persisting viral infection. T-bet in B cells controlled IgG2a production, as well as mucosal localization, proliferation, glycosylation, and a broad transcriptional program...
August 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Martin S Naradikian, Arpita Myles, Daniel P Beiting, Kenneth J Roberts, Lucas Dawson, Ramin Sedaghat Herati, Bertram Bengsch, Susanne L Linderman, Erietta Stelekati, Rosanne Spolski, E John Wherry, Christopher Hunter, Scott E Hensley, Warren J Leonard, Michael P Cancro
T-bet and CD11c expression in B cells is linked with IgG2c isotype switching, virus-specific immune responses, and humoral autoimmunity. However, the activation requisites and regulatory cues governing T-bet and CD11c expression in B cells remain poorly defined. In this article, we reveal a relationship among TLR engagement, IL-4, IL-21, and IFN-γ that regulates T-bet expression in B cells. We find that IL-21 or IFN-γ directly promote T-bet expression in the context of TLR engagement. Further, IL-4 antagonizes T-bet induction...
August 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Timothy J Nice, Lisa C Osborne, Vesselin T Tomov, David Artis, E John Wherry, Herbert W Virgin
In order for a virus to persist, there must be a balance between viral replication and immune clearance. It is commonly believed that adaptive immunity drives clearance of viral infections and, thus, dysfunction or viral evasion of adaptive immunity is required for a virus to persist. Type I interferons (IFNs) play pleiotropic roles in the antiviral response, including through innate control of viral replication. Murine norovirus (MNoV) replicates in dendritic cells (DCs) and type I IFN signaling in DCs is important for early control of MNoV replication...
June 2016: PLoS Pathogens
John Attanasio, E John Wherry
Costimulatory and inhibitory receptors play a key role in regulating immune responses to infections. Recent translation of knowledge about inhibitory receptors such as CTLA-4 and PD-1 into the cancer clinic highlights the opportunities to manipulate these pathways to treat human disease. Studies in infectious disease have provided key insights into the specific roles of these pathways and the effects of their manipulation. Here, recent studies are discussed that have addressed how major inhibitory and costimulatory pathways play a role in regulating immune responses during acute and chronic infections...
May 17, 2016: Immunity
Andy J Minn, E John Wherry
Improving efficacy of immune checkpoint blockade for cancer can be facilitated by combining these agents with each other and/or with other conventional or targeted therapies. Interferon and innate immune signaling pathways in immune and tumor cells have emerged as intriguing determinants of response and resistance, often in complex and seemingly paradoxical ways.
April 7, 2016: Cell
Ira Mellman, Vanessa M Hubbard-Lucey, Matthew J Tontonoz, Michael D Kalos, Daniel S Chen, James P Allison, Charles G Drake, Hy Levitsky, Nils Lonberg, Sjoerd H van der Burg, Douglas T Fearon, E John Wherry, Israel Lowy, Robert H Vonderheide, Patrick Hwu
With the recent FDA approvals of pembrolizumab and nivolumab, and a host of additional immunomodulatory agents entering clinical development each year, the field of cancer immunotherapy is changing rapidly. Strategies that can assist researchers in choosing the most promising drugs and drug combinations to move forward through clinical development are badly needed in order to reduce the likelihood of late-stage clinical trial failures. On October 5, 2014, the Cancer Immunotherapy Consortium of the Cancer Research Institute, a collaborative think tank composed of stakeholders from academia, industry, regulatory agencies, and patient interest groups, met to discuss strategies for de-risking immunotherapy development, with a focus on integrating preclinical and clinical studies, and conducting smarter early-phase trials, particularly for combination therapies...
April 2016: Cancer Immunology Research
Catherine Riou, Natalie Strickland, Andreia P Soares, Björn Corleis, Douglas S Kwon, E John Wherry, Robert J Wilkinson, Wendy A Burgers
HIV-infected persons are at greater risk of developing tuberculosis (TB) even before profound CD4 loss occurs, suggesting that HIV alters CD4(+) T cell functions capable of containing bacterial replication. An effective immune response to Mycobacterium tuberculosis most likely relies on the development of a balanced CD4 response, in which distinct CD4(+) Th subsets act in synergy to control the infection. To define the diversity of M. tuberculosis-specific CD4(+) Th subsets and determine whether HIV infection impacts such responses, the expression of lineage-defining transcription factors T-bet, Gata3, RORγt, and Foxp3 was measured in M...
April 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Kristen E Pauken, E John Wherry
No abstract text is available yet for this article.
November 5, 2015: Cell
Jang Eun Lee, Matthew C Walsh, Kyle L Hoehn, David E James, E John Wherry, Yongwon Choi
Differentiation of T cells is closely associated with dynamic changes in nutrient and energy metabolism. However, the extent to which specific metabolic pathways and molecular components are determinative of CD8+ T cell fate remains unclear. It has been previously established in various tissues that acetyl CoA carboxylase 2 (ACC2) regulates fatty acid oxidation (FAO) by inhibiting carnitine palmitoyltransferase 1 (CPT1), a rate-limiting enzyme of FAO in mitochondria. Here, we explore the cell-intrinsic role of ACC2 in T cell immunity in response to infections...
2015: PloS One
Erika J Crosby, Megan Clark, Fernanda O Novais, E John Wherry, Phillip Scott
Leishmaniasis is a significant neglected tropical disease that is associated with a wide range of clinical presentations and a lifelong persistent infection. Because of the chronic nature of the disease, there is a high risk for coinfection occurring in patients, and how coinfections influence the outcome of leishmaniasis is poorly understood. To address this issue, we infected mice with Leishmania major and 2 wk later with lymphocytic choriomeningitis virus (LCMV) and then monitored the course of infection...
October 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
E John Wherry, Makoto Kurachi
In chronic infections and cancer, T cells are exposed to persistent antigen and/or inflammatory signals. This scenario is often associated with the deterioration of T cell function: a state called 'exhaustion'. Exhausted T cells lose robust effector functions, express multiple inhibitory receptors and are defined by an altered transcriptional programme. T cell exhaustion is often associated with inefficient control of persisting infections and tumours, but revitalization of exhausted T cells can reinvigorate immunity...
August 2015: Nature Reviews. Immunology
Daniel P Beiting, Shinya Hidano, Julie E Baggs, Jeanne M Geskes, Qun Fang, E John Wherry, Christopher A Hunter, David S Roos, Sara Cherry
The protozoan parasite, Toxoplasma, like many intracellular pathogens, suppresses interferon gamma (IFN-γ)-induced signal transducer and activator of transcription 1 (STAT1) activity. We exploited this well-defined host-pathogen interaction as the basis for a high-throughput screen, identifying nine transcription factors that enhance STAT1 function in the nucleus, including the orphan nuclear hormone receptor TLX. Expression profiling revealed that upon IFN-γ treatment TLX enhances the output of a subset of IFN-γ target genes, which we found is dependent on TLX binding at those loci...
July 2015: PLoS Biology
Pamela M Odorizzi, Kristen E Pauken, Michael A Paley, Arlene Sharpe, E John Wherry
Programmed Death-1 (PD-1) has received considerable attention as a key regulator of CD8(+) T cell exhaustion during chronic infection and cancer because blockade of this pathway partially reverses T cell dysfunction. Although the PD-1 pathway is critical in regulating established "exhausted" CD8(+) T cells (TEX cells), it is unclear whether PD-1 directly causes T cell exhaustion. We show that PD-1 is not required for the induction of exhaustion in mice with chronic lymphocytic choriomeningitis virus (LCMV) infection...
June 29, 2015: Journal of Experimental Medicine
Carolina Pombo, E John Wherry, Emma Gostick, David A Price, Michael R Betts
During chronic human immunodeficiency virus (HIV) infection, virus-specific CD8(+) T cells become functionally exhausted. Unlike most chronically infected individuals, elite controllers of HIV retain CD8(+) T-cell polyfunctionality and cytolytic capacity. It remains unclear whether elite controllers manifest T-cell exhaustion similar to subjects with chronic progression of HIV infection. Here we assessed coexpression of PD-1, Lag-3, CD160, and 2B4 as a measure of T-cell exhaustion in a cohort of elite controllers and in chronic progressors...
November 1, 2015: Journal of Infectious Diseases
Katrin Schlie, Ashley Westerback, Lindsay DeVorkin, Luke R Hughson, Jillian M Brandon, Sarah MacPherson, Izabelle Gadawski, Katelin N Townsend, Vincent I Poon, Mary A Elrick, Helene C F Côté, Ninan Abraham, E John Wherry, Noboru Mizushima, Julian J Lum
The activation and expansion of effector CD8(+) T cells are essential for controlling viral infections and tumor surveillance. During an immune response, T cells encounter extrinsic and intrinsic factors, including oxidative stress, nutrient availability, and inflammation, that can modulate their capacity to activate, proliferate, and survive. The dependency of T cells on autophagy for in vitro and in vivo activation, expansion, and memory remains unclear. Moreover, the specific signals and mechanisms that activate autophagy in T effector cells and their survival are not known...
May 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Saumil J Gandhi, Andy J Minn, Robert H Vonderheide, E John Wherry, Stephen M Hahn, Amit Maity
The importance of ionizing radiation has historically been limited to achieving local control of tumor cells. However, emerging evidence over the last decade suggests an increasingly important role for radiation in amplifying the antitumor immune response elicited by immunomodulatory agents. Combination of radiation with immunotherapy has been shown to elicit powerful systemic responses in several pre-clinical tumor models. Additionally, recent clinical observations support the use of radiation therapy for augmenting antitumor immunity in the metastatic setting...
November 28, 2015: Cancer Letters
Kristen E Pauken, E John Wherry
Inhibitors of the Programmed Cell Death 1: Programmed Cell Death 1 ligand 1 (PD-1:PD-L1) pathway, a central regulator of T cell exhaustion, have been recently shown to be effective for treatment of different cancers. However, clinical responses are mixed, highlighting the need to better understand the mechanisms of action of PD-1:PD-L1, the role of this pathway in immunity to different tumors, and the molecular and cellular effects of PD-1 blockade. Here, we review the molecular regulation of T cell exhaustion, placing recent findings on PD-1 blockade therapies in cancer in the context of the broader understanding of the roles of the PD-1:PD-L1 pathway in T cell exhaustion during chronic infection...
April 2015: Trends in Immunology
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