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Gavin M Lewis, Ellen J Wehrens, Lara Labarta-Bajo, Hendrik Streeck, Elina I Zuniga
Suppression of CD8 and CD4 T cells is a hallmark in chronic viral infections, including hepatitis C and HIV. While multiple pathways are known to inhibit CD8 T cells, the host molecules that restrict CD4 T cell responses are less understood. Here, we used inducible and CD4 T cell-specific deletion of the gene encoding the TGF-β receptor during chronic lymphocytic choriomeningitis virus infection in mice, and determined that TGF-β signaling restricted proliferation and terminal differentiation of antiviral CD4 T cells...
October 3, 2016: Journal of Clinical Investigation
Rong Wang, Yuki Kang, Christiane V Löhr, Kay A Fischer, C Samuel Bradford, Gavin Johnson, Wan Mohaiza Dashwood, David E Williams, Emily Ho, Roderick H Dashwood
Eomesodermin (Eomes) is a T-box transcription factor that has been implicated in the etiology of colorectal cancer and other human malignancies. We screened a panel of human primary colon cancers and patient-matched controls (n = 30) and detected Eomes overexpression at the mRNA and protein level. Similar results were obtained in a panel of rat colon tumors and adjacent normal-looking colonic mucosa (n = 24). In human colon cancer cells, forced overexpression of Eomes enhanced cell viability and protected against staurosporine-induced apoptosis...
October 28, 2016: Cancer Letters
Korey R Demers, George Makedonas, Marcus Buggert, Michael A Eller, Sarah J Ratcliffe, Nilu Goonetilleke, Chris K Li, Leigh Anne Eller, Kathleen Rono, Lucas Maganga, Sorachai Nitayaphan, Hannah Kibuuka, Jean-Pierre Routy, Mark K Slifka, Barton F Haynes, Andrew J McMichael, Nicole F Bernard, Merlin L Robb, Michael R Betts
The loss of HIV-specific CD8+ T cell cytolytic function is a primary factor underlying progressive HIV infection, but whether HIV-specific CD8+ T cells initially possess cytolytic effector capacity, and when and why this may be lost during infection, is unclear. Here, we assessed CD8+ T cell functional evolution from primary to chronic HIV infection. We observed a profound expansion of perforin+ CD8+ T cells immediately following HIV infection that quickly waned after acute viremia resolution. Selective expression of the effector-associated transcription factors T-bet and eomesodermin in cytokine-producing HIV-specific CD8+ T cells differentiated HIV-specific from bulk memory CD8+ T cell effector expansion...
August 2016: PLoS Pathogens
Nathalie Schmitt, Yang Liu, Salah-Eddine Bentebibel, Hideki Ueno
IL-12 is important for the differentiation of T follicular helper (Tfh) cells, as well as Th1 cells in humans. Still, how IL-12 signals regulate Tfh versus Th1 cell differentiation remains poorly characterized. Here we aimed to determine the molecular mechanisms that regulate the differentiation and the function of IL-12-stimulated human naive CD4(+) T cells. We found that T-bet promoted the expression of CXCR5 in human CD4(+) T cells. We provide evidence that T-bet does not strongly inhibit the Tfh cell differentiation program per se but diminishes the functions to provide help to B cells...
July 26, 2016: Cell Reports
Na Cui, Long-Xiang Su, Hao Wang, Meng Xiao, Fei Yang, Min Zheng, Xin Li, Ying-Chun Xu, Da-Wei Liu
BACKGROUND: Aspergillosis infection is common in the patients with insufficient immunity. The role of mammalian target of rapamycin (mTOR), T-box expressed in T-cells (T-bet), and eomesodermin (EOMES) in mediating T lymphocytes differentiation in response to Aspergillus fumigatus infection in immunocompromised rats was investigated in this study. METHODS: Invasive pulmonary aspergillosis (IPA) of immunosuppressive twenty male rats were established and sacrificed at 24 h (n = 5), 48 h (n = 5), 72 h (n = 5), and 96 h (n = 5) after A...
July 20, 2016: Chinese Medical Journal
Victor Cortez, Marco Colonna
Innate lymphoid cells (ILCs) are a heterogeneous population of cells with diverse roles in immune responses. Three major groups of ILCs have been defined on the basis of similarity in their production of signature cytokines, developmental requirements, and phenotypic markers. Group 1 ILCs produce IFN-γ, express the T-box transcription factors (TF) Eomesodermin (Eomes) and/or T-bet. Group 2 ILCs secrete IL-5 and IL-13, express the TF GATA-3, and are identified by the expression of KLRG1, the receptor IL-7 (IL7R, also known as CD127), and the receptor for IL-33 (IL33R)...
July 6, 2016: Immunology Letters
Federico Simonetta, Amandine Pradier, Eddy Roosnek
Recent reports give insights into the role of the T-box transcription factors, T-bet and Eomesodermin (Eomes), in NK cell biology. In this mini-review, we recapitulate the initial reports that delineate T-bet and Eomes as master regulators of NK cell development, maturation, and function. We discuss how T-bet and Eomes expression is regulated during NK cell development and peripheral maturation. Furthermore, we summarize the current literature on the role of T-bet and Eomes in the transcriptional regulation of NK cell function and review possible effects of T-box transcription factor anomalies during aging, infection, cancer, and after hematopoietic stem cell transplantation...
2016: Frontiers in Immunology
Elena V Shashkova, Jahnavi Trivedi, Anna B Cline-Smith, Chloe Ferris, Zachary S Buchwald, Jesse Gibbs, Deborah Novack, Rajeev Aurora
Osteoimmunology arose from the recognition that cytokines produced by lymphocytes can affect bone homeostasis. We have previously shown that osteoclasts, cells that resorb bone, act as APCs. Cross-presentation of Ags by osteoclasts leads to expression of CD25 and Foxp3, markers of regulatory T cells in the CD8 T cells. Octeoclast-induced Foxp3(+) CD25(+) regulatory CD8 T cells (OC-iTcREG) suppress priming of CD4 and CD8 T cells by dendritic cells. OC-iTcREG also limit bone resorption by osteoclasts, forming a negative feedback loop...
August 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Kristin R Renkema, June-Yong Lee, You Jeong Lee, Sara E Hamilton, Kristin A Hogquist, Stephen C Jameson
Previous studies have revealed that a population of innate memory CD8(+) T cells is generated in response to IL-4, first appearing in the thymus and bearing high expression levels of Eomesodermin (Eomes) but not T-bet. However, the antigen specificity and functional properties of these cells is poorly defined. In this study, we show that IL-4 regulates not only the frequency and function of innate memory CD8(+) T cells, but also regulates Eomes expression levels and functional reactivity of naive CD8(+) T cells...
June 27, 2016: Journal of Experimental Medicine
Shinji Oki
  Development of acute experimental autoimmune encephalomyelitis (EAE) depends on Th17 cells expressing the nuclear factor NR4A2, which we have previously reported to be upregulated in peripheral blood T cells from patients of multiple sclerosis (MS). EAE induced in mice lacking NR4A2 in T cells showed a great reduction in Th17-mediated acute symptoms, whereas a late-onset disease independent of NR4A2 was still inducible. We identified cytotoxic T-cell-like CD4+ T cells expressing the T-box transcription factor Eomesodermin (Eomes) as a pathogenic component for the development of the late-onset disease...
2016: Nihon Rinshō Men'eki Gakkai Kaishi, Japanese Journal of Clinical Immunology
Hi-Jung Park, Ara Lee, Jae-Il Lee, Seong Hoe Park, Sang-Jun Ha, Kyeong Cheon Jung
Unlike conventional T cells, innate CD8 T cells develop a memory-like phenotype in the thymus and immediately respond upon antigen stimulation, similar to memory T cells. The development of innate CD8 T cells in the thymus is known to require IL-4, which upregulates Eomesodermin (Eomes). These features are similar to that of virtual memory CD8 T cells and IL-4-induced memory-like CD8 T cells generated in the peripheral tissues. However, the relationship between these cell types has not been clearly documented...
April 2016: Immune Network
Aizhang Xu, Kalpana Kalyanasundaram Bhanumathy, Jie Wu, Zhenmin Ye, Andrew Freywald, Scot C Leary, Rongxiu Li, Jim Xiang
BACKGROUND: Lymphopenia promotes naïve T-cell homeostatic proliferation and adoptive effector T-cell survival and memory formation. IL-7 plays a critical role in homeostatic proliferation, survival and memory formation of naïve T-cells in lymphopenia, and its underlying molecular mechanism has also been well studied. However, the mechanism for adoptively transferred effector T-cell survival and memory formation is not fully understood. Here, we transferred in vitro-activated transgenic OT-I CD8(+) effector T-cells into irradiation (600 rads)-induced lymphopenic C57BL/6, IL-7 knockout (KO) and IL-15 KO mice, and investigated the survival and memory formation of transferred T-cells in lymphopenia...
2016: Cell & Bioscience
Simon Völkl, Anne Rensing-Ehl, Andrea Allgäuer, Elisabeth Schreiner, Myriam Ricarda Lorenz, Jan Rohr, Christian Klemann, Ilka Fuchs, Volker Schuster, André O von Bueren, Nora Naumann-Bartsch, Eleonora Gambineri, Kathrin Siepermann, Robin Kobbe, Michaela Nathrath, Peter D Arkwright, Maurizio Miano, Klaus-Daniel Stachel, Markus Metzler, Klaus Schwarz, Anita N Kremer, Carsten Speckmann, Stephan Ehl, Andreas Mackensen
Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCRαβ(+) CD4(-) CD8(-) double-negative T (DNT) cells. Although their phenotype resembles that of terminally differentiated or exhausted T cells, lack of KLRG1, high eomesodermin, and marginal T-bet expression point instead to a long-lived memory state with potent proliferative capacity. Here we show that despite their terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in vivo...
July 14, 2016: Blood
Øyvind Dahle, Michael R Kuehn
BACKGROUND: Pluripotent embryonic stem cells (ESCs) offer great potential for regenerative medicine. However, efficient in vitro generation of specific desired cell types is still a challenge. We previously established that Smad2/3 signaling, essential for endoderm formation, regulates target gene expression by counteracting epigenetic repression mediated by Polycomb Repressive Complex 2 (PRC2). Although this mechanism has been demonstrated during differentiation and reprogramming, little is known of its role in pluripotent cells...
July 2016: Developmental Dynamics: An Official Publication of the American Association of Anatomists
Xiuli Wang, ChingLam W Wong, Ryan Urak, Ellie Taus, Brenda Aguilar, Wen-Chung Chang, Armen Mardiros, Lihua E Budde, Christine E Brown, Carolina Berger, Stephen J Forman, Michael C Jensen
Human CD8(+) effector T cells derived from CD45RO(+)CD62L(+) precursors enriched for central memory (TCM) precursors retain the capacity to engraft and reconstitute functional memory upon adoptive transfer, whereas effectors derived from CD45RO(+)CD62L(-) precursors enriched for effector memory precursors do not. Here we sought to compare the engraftment fitness and function of CD8(+) effector T cells derived from CD45RA(+)CD62L(+) precursors enriched for naïve and stem cell memory precursors (TN/SCM) with that of TCM...
2016: Oncoimmunology
Irene M Rodríguez-Gómez, Stephanie C Talker, Tobias Käser, Maria Stadler, Sabine E Hammer, Armin Saalmüller, Wilhelm Gerner
The transcription factors GATA-3, T-bet and Eomesodermin play important roles in T-cell development, differentiation and memory formation. However, their expression has not been studied in great detail in porcine T cells. We report on protein expression at the single cell-level of these transcription factors in thymocytes and mature αβ T cells. GATA-3 expression was found in γδ(-) thymocytes, with decreasing expression from the CD4(-)CD8α(-) stage towards single-positive stages. Extra-thymic CD4(+) T cells but not CD8β(+) T cells expressed low levels of GATA-3, which decreased with age...
July 2016: Developmental and Comparative Immunology
Katherine A Deets, Amy M Berkley, Tessa Bergsbaken, Pamela J Fink
The youngest peripheral T cells (recent thymic emigrants [RTEs]) are functionally distinct from naive T cells that have completed postthymic maturation. We assessed the RTE memory response and found that RTEs produced less granzyme B than their mature counterparts during infection but proliferated more and, therefore, generated equivalent target killing in vivo. Postinfection, RTE numbers contracted less dramatically than those of mature T cells, but RTEs were delayed in their transition to central memory, displaying impaired expression of CD62L, IL-2, Eomesodermin, and CXCR4, which resulted in impaired bone marrow localization...
March 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Na Cui, Longxiang Su, Meng Xiao, Fei Yang, Dawei Liu
OBJECTIVE: To investigate the function of triggering receptor expresses on myeloid cells receptor-1 (TREM-1) in lymphocyte differentiation and regulation of Aspergillus infected immunosuppressed rats. METHODS: Cyclophosphamide (CTX) was intraperitoneally injected and Fumigatus spore suspension was inhaled by percutaneous tracheostomy to establish the immunosuppressive invasive pulmonary aspergillosis (IPA) rat model. After 24 h, 48 h, 72 h and 96 h inoculation, rats were sacrificed...
January 2016: Zhonghua Nei Ke za Zhi [Chinese Journal of Internal Medicine]
Olga Pikovskaya, Julie Chaix, Nyanza J Rothman, Amélie Collins, Yen-Hua Chen, Anna M Scipioni, Eric Vivier, Steven L Reiner
Type 1 innate lymphocytes comprise two developmentally divergent lineages, type 1 helper innate lymphoid cells (hILC1s) and conventional NK cells (cNKs). All type 1 innate lymphocytes (ILCs) express the transcription factor T-bet, but cNKs additionally express Eomesodermin (Eomes). We show that deletion of Eomes alleles at the onset of type 1 ILC maturation using NKp46-Cre imposes a substantial block in cNK development. Formation of the entire lymphoid and nonlymphoid type 1 ILC compartment appears to require the semiredundant action of both T-bet and Eomes...
February 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Ribhu Nayar, Elizabeth Schutten, Sonal Jangalwe, Philip A Durost, Laurie L Kenney, James M Conley, Keith Daniels, Michael A Brehm, Raymond M Welsh, Leslie J Berg
CD8+ T cell exhaustion commonly occurs in chronic infections and cancers. During T cell exhaustion there is a progressive and hierarchical loss of effector cytokine production, up-regulation of inhibitory co-stimulatory molecules, and eventual deletion of antigen specific cells by apoptosis. A key factor that regulates T cell exhaustion is persistent TCR stimulation. Loss of this interaction results in restoration of CD8+ T cell effector functions in previously exhausted CD8+ T cells. TCR stimulation is also important for the differentiation of Eomeshi anti-viral CD8+ effector T cells from T-bethi precursors, both of which are required for optimal viral control...
2015: PloS One
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