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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...
January 2, 2018: Journal of Experimental Medicine
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
R N Nair, J J Rosnow, T A Murphree, M E Bowden, S R Lindemann, A T Wright
De novo synthesis of alkynalted tryptophan moieties as chemical probes for protein profilling studies, via an unexpected synthesis of Michael acceptor 12 is reported. Friedel Craft's alkylation of 12 and alkyne substituted indoles gave alkynalated tryptophan moieties, which perform as chemical probe by incorporating into actively translating Escherichia coli cells, whereby the alkyne moiety enables multimodal analyses through click chemistry mediated attachment of reporting groups.
April 1, 2017: Organic Chemistry Frontiers: An International Journal of Organic Chemistry
Jesse W Williams, Andrew Elvington, Stoyan Ivanov, Skyler Kessler, Hannah Luehmann, Osamu Baba, Brian T Saunders, Ki-Wook Kim, Michael W Johnson, Clarissa S Craft, Jae-Hoon Choi, Mary G Sorci-Thomas, Bernd H Zinselmeyer, Jonathan R Brestoff, Yongjian Liu, Gwendalyn J Randolph
RATIONALE: Ambient temperature is a risk factor for cardiovascular disease. Cold weather increases cardiovascular events, but paradoxically, cold exposure is metabolically protective because of UCP1 (uncoupling protein 1)-dependent thermogenesis. OBJECTIVE: We sought to determine the differential effects of ambient environmental temperature challenge and UCP1 activation in relation to cardiovascular disease progression. METHODS AND RESULTS: Using mouse models of atherosclerosis housed at 3 different ambient temperatures, we observed that cold temperature enhanced, whereas thermoneutral housing temperature inhibited atherosclerotic plaque growth, as did deficiency in UCP1...
September 1, 2017: Circulation Research
Lidia Bosurgi, Y Grace Cao, Mar Cabeza-Cabrerizo, Andrea Tucci, Lindsey D Hughes, Yong Kong, Jason S Weinstein, Paula Licona-Limon, Edward T Schmid, Facundo Pelorosso, Nicola Gagliani, Joseph E Craft, Richard A Flavell, Sourav Ghosh, Carla V Rothlin
Tissue repair is a subset of a broad repertoire of interleukin-4 (IL-4)- and IL-13-dependent host responses during helminth infection. Here we show that IL-4 or IL-13 alone was not sufficient, but IL-4 or IL-13 together with apoptotic cells induced the tissue repair program in macrophages. Genetic ablation of sensors of apoptotic cells impaired the proliferation of tissue-resident macrophages and the induction of anti-inflammatory and tissue repair genes in the lungs after helminth infection or in the gut after induction of colitis...
June 9, 2017: Science
Joseph A Trapani, Phillip K Darcy
BACKGROUND: For 50 years, cancer physicians have relied on just three primary treatment modalities: surgery, radiation therapy and chemotherapy. Over that time, enormous progress has been made in understanding cancer biology, targeted anti-cancer drugs have emerged, and thousands of clinical trials have taught us how best to craft treatment combinations that improve clinical outcomes. Only five years ago, a fourth and radically different form of therapy finally emerged: immune‑based cancer therapies...
2017: Australian Family Physician
Jin-Young Choi, Abhinav Seth, Michael Kashgarian, Sonia Terrillon, Emma Fung, Lili Huang, Li Chun Wang, Joe Craft
Systemic lupus erythematosus (lupus) is characterized by autoantibody-mediated organ injury. Follicular Th (Tfh) cells orchestrate physiological germinal center (GC) B cell responses, whereas in lupus they promote aberrant GC responses with autoreactive memory B cell development and plasma cell-derived autoantibody production. IL-21, a Tfh cell-derived cytokine, provides instructional cues for GC B cell maturation, with disruption of IL-21 signaling representing a potential therapeutic strategy for autoantibody-driven diseases such as systemic lupus erythematosus...
April 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Marc Douaisi, Rachel S Resop, Maho Nagasawa, Joshua Craft, Beth D Jamieson, Bianca Blom, Christel H Uittenbogaart
Although CD31 expression on human thymocytes has been reported, a detailed analysis of CD31 expression at various stages of T cell development in the human thymus is missing. In this study, we provide a global picture of the evolution of CD31 expression from the CD34(+) hematopoietic precursor to the CD45RA(+) mature CD4(+) and CD8(+) single-positive (SP) T cells. Using nine-color flow cytometry, we show that CD31 is highly expressed on CD34(+) progenitors and stays high until the early double-positive stage (CD3(-)CD4(+)CD8α(+)β(-))...
March 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
P Singh, T Saha, P Mishra, M K Parai, S Ireddy, S Lavanya Kumar M, S Krishna, S K Kumar, V Chaturvedi, S Sinha, M I Siddiqi, G Panda
We earlier reported thiophene-containing trisubstituted methanes (TRSMs) as novel cores carrying anti-tubercular activity, and identified S006-830 as the phenotypic lead with potent bactericidal activity against single- and multi-drug resistant clinical isolates of Mycobacterium tuberculosis (M. tb). In this work, we carried out additional synthesis of several TRSMs. The reaction scheme essentially followed the Grignard reaction and Friedel-Crafts alkylation, followed by insertion of a dialkylaminoethyl chain...
November 2016: SAR and QSAR in Environmental Research
Patrick Cherubin, Maria Camila Garcia, David Curtis, Christopher B T Britt, John W Craft, Helen Burress, Chris Berndt, Srikar Reddy, Jessica Guyette, Tianyu Zheng, Qun Huo, Beatriz Quiñones, James M Briggs, Ken Teter
Cholera toxin (CT) is an AB-type protein toxin that contains a catalytic A1 subunit, an A2 linker, and a cell-binding B homopentamer. The CT holotoxin is released into the extracellular environment, but CTA1 attacks a target within the cytosol of a host cell. We recently reported that grape extract confers substantial resistance to CT. Here, we used a cell culture system to identify twelve individual phenolic compounds from grape extract that inhibit CT. Additional studies determined the mechanism of inhibition for a subset of the compounds: two inhibited CT binding to the cell surface and even stripped CT from the plasma membrane of a target cell; two inhibited the enzymatic activity of CTA1; and four blocked cytosolic toxin activity without directly affecting the enzymatic function of CTA1...
2016: PloS One
Li Ren, Yang Yu, Li Wang, Zhifeng Zhu, Rong Lu, Zhi Yao
Tumor cells craft microenvironment to overcome growth disadvantages and adjust to escape the immunosurveillance during tumorigenesis and metastasis. The evolving adaption to the changing microenvironment is exemplified by the development of strategies to deal with hypoxia resulted from fast proliferation of the tumor cells. In this study, we found that hypoxia hepatocellular carcinoma (HCC) cells recruited Regulatory T cells (Tregs) and expressed more Chemokine (C-C motif) ligand 28 (CCL28). Deletion of CCL28 inhibited Treg recruitment...
November 15, 2016: Oncotarget
Mary F Fontana, Alyssa Baccarella, Joshua F Craft, Michelle J Boyle, Tara I McIntyre, Matthew D Wood, Kurt S Thorn, Chioma Anidi, Aqieda Bayat, Me Ree Chung, Rebecca Hamburger, Chris Y Kim, Emily Pearman, Jennifer Pham, Jia J Tang, Louis Boon, Moses R Kamya, Grant Dorsey, Margaret E Feeney, Charles C Kim
In humans, immunity to Plasmodium sp. generally takes the form of protection from symptomatic malaria (i.e., 'clinical immunity') rather than infection ('sterilizing immunity'). In contrast, mice infected with Plasmodium develop sterilizing immunity, hindering progress in understanding the mechanistic basis of clinical immunity. Here we present a novel model in which mice persistently infected with P. chabaudi exhibit limited clinical symptoms despite sustaining patent parasite burdens for many months. Characterization of immune responses in persistently infected mice revealed development of CD4+ T cell exhaustion, increased production of IL-10, and expansion of B cells with an atypical surface phenotype...
2016: PloS One
Jason S Weinstein, Edward I Herman, Begoña Lainez, Paula Licona-Limón, Enric Esplugues, Richard Flavell, Joe Craft
Germinal center (GC) B cells undergo affinity selection, which depends on interactions with CD4(+) follicular helper T cells (TFH cells). We found that TFH cells progressed through transcriptionally and functionally distinct stages and provided differential signals for GC regulation. They initially localized proximally to mutating B cells, secreted interleukin 21 (IL-21), induced expression of the transcription factor Bcl-6 and selected high-affinity B cell clones. As the GC response evolved, TFH cells extinguished IL-21 production and switched to IL-4 production, showed robust expression of the co-stimulatory molecule CD40L, and promoted the development of antibody-secreting B cells via upregulation of the transcription factor Blimp-1...
October 2016: Nature Immunology
Marilia S Santos, Daniara C Fernandes, Manoel T Rodrigues, Thais Regiani, Adriano D Andricopulo, Ana Lúcia T G Ruiz, Débora B Vendramini-Costa, João E de Carvalho, Marcos N Eberlin, Fernando Coelho
The cyclopenta[b]indole motif is present in several natural and synthetic biologically active compounds, being directly responsible for the biological effects some of them present. We described herein a three step sequence for the synthesis of cyclopenta[b]indoles with a great structural diversity. The method is based on an oxidative Michael addition of suitable indoles on the double bond of Morita-Baylis-Hillman adducts mediated by a hypervalent iodine reagent (IBX) to form β-ketoesters, which were chemoselectively reduced with NaBH4 in THF to give the corresponding β-hydroxy-esters...
August 5, 2016: Journal of Organic Chemistry
Stephen R F Twigg, Robert B Hufnagel, Kerry A Miller, Yan Zhou, Simon J McGowan, John Taylor, Jude Craft, Jenny C Taylor, Stephanie L Santoro, Taosheng Huang, Robert J Hopkin, Angela F Brady, Jill Clayton-Smith, Carol L Clericuzio, Dorothy K Grange, Leopold Groesser, Christian Hafner, Denise Horn, I Karen Temple, William B Dobyns, Cynthia J Curry, Marilyn C Jones, Andrew O M Wilkie
Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling...
June 2, 2016: American Journal of Human Genetics
Rachel S Resop, Marc Douaisi, Joshua Craft, Loes C M Jachimowski, Bianca Blom, Christel H Uittenbogaart
BACKGROUND: The mechanisms that govern the egress of mature thymocytes from the human thymus to the periphery remain understudied yet are of utmost importance to the field of basic immunology, as well as T-cell reconstitution in various immunodeficiencies. We examined the expression and function of sphingosine-1-phosphate (S1P) receptors in human thymocyte egress. OBJECTIVES: We aimed to determine whether S1P receptors (S1P-Rs) play a role in mature human thymocyte egress and to identify the thymocyte population or populations that express S1P-Rs and respond to S1P by migrating across a concentration gradient...
August 2016: Journal of Allergy and Clinical Immunology
Pamela Y Chan, Eugenio A Carrera Silva, Dimitri De Kouchkovsky, Leonel D Joannas, Liming Hao, Donglei Hu, Scott Huntsman, Celeste Eng, Paula Licona-Limón, Jason S Weinstein, De'Broski R Herbert, Joseph E Craft, Richard A Flavell, Silvia Repetto, Jorge Correale, Esteban G Burchard, Dara G Torgerson, Sourav Ghosh, Carla V Rothlin
Host responses against metazoan parasites or an array of environmental substances elicit type 2 immunity. Despite its protective function, type 2 immunity also drives allergic diseases. The mechanisms that regulate the magnitude of the type 2 response remain largely unknown. Here, we show that genetic ablation of a receptor tyrosine kinase encoded byTyro3in mice or the functional neutralization of its ortholog in human dendritic cells resulted in enhanced type 2 immunity. Furthermore, the TYRO3 agonist PROS1 was induced in T cells by the quintessential type 2 cytokine, interleukin-4...
April 1, 2016: Science
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
Eric Peatman, Miles Lange, Honggang Zhao, Benjamin H Beck
The mucosal barriers of catfish (Ictalurus spp) constitute the first line of defense against pathogen invasion while simultaneously carrying out a diverse array of other critical physiological processes, including nutrient adsorption, osmoregulation, waste excretion, and environmental sensing. Catfish depend more heavily on mucosal barriers than their terrestrial counterparts as they are continuously interacting with the aquatic microbiota. Our understanding of these barriers, while growing, is still limited relative to that of mammalian model systems...
October 2015: Tissue Barriers
Janise D Deming, Joseph S Pak, Jung-A Shin, Bruce M Brown, Moon K Kim, Moe H Aung, Eun-Jin Lee, Machelle T Pardue, Cheryl Mae Craft
PURPOSE: Previous studies discovered cone phototransduction shutoff occurs normally for Arr1-/- and Arr4-/-; however, it is defective when both visual arrestins are simultaneously not expressed (Arr1-/-Arr4-/-). We investigated the roles of visual arrestins in an all-cone retina (Nrl-/-) since each arrestin has differential effects on visual function, including ARR1 for normal light adaptation, and ARR4 for normal contrast sensitivity and visual acuity. METHODS: We examined Nrl-/-, Nrl-/-Arr1-/-, Nrl-/-Arr4-/-, and Nrl-/-Arr1-/-Arr4-/- mice with photopic electroretinography (ERG) to assess light adaptation and retinal responses, immunoblot and immunohistochemical localization analysis to measure retinal expression levels of M- and S-opsin, and optokinetic tracking (OKT) to measure the visual acuity and contrast sensitivity...
December 2015: Investigative Ophthalmology & Visual Science
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