37 results on '"Dent, Alexander L."'
Search Results
2. Regulation of gene expression by the proto-oncogene BCL-6
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Dent, Alexander L., Vasanwala, Farha H., and Toney, Lisa M.
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GENE expression , *LYMPHOMAS , *B cells - Abstract
The proto-oncogene BCL-6 encodes a transcriptional repressor protein that is expressed at high levels in germinal center B cells and lymphomas with a germinal center B cell phenotype. The BCL-6 gene is a frequent target of chromosomal translocations, micro-deletions, and point mutations in non-Hodgkin''s lymphoma. Studies of BCL-6-deficient mice have revealed that BCL-6 is critical for normal lymphocyte differentiation and also that BCL-6 is a negative regulator of inflammation. Recent studies have shed light on how BCL-6 controls these processes by showing that BCL-6 regulates a broad spectrum of target genes. BCL-6 represses transcription of genes involved in lymphocyte activation, differentiation, proliferation, and migration. Although much progress has been made in understanding gene regulation by BCL-6, many important questions are unresolved. [Copyright &y& Elsevier]
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- 2002
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3. T helper type 2 inflammatory disease in the absence of interleukin 4 and transcription factor STAT6.
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Dent, Alexander L. and Hu-Li, Jane
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T cells , *INTERLEUKIN-4 , *TRANSCRIPTION factors - Abstract
Presents a study on T helper type 2 inflammatory disease in the absence of interleukin 4 and transcription factor STAT6. Differentiation of CD4 T helper cells into T helper type 1 or 2; Materials and methods used in the study; Results.
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- 1998
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4. Control of inflammation, cytokine expression, and germinal center formation by BCL-6.
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Dent, Alexander L. and Shaffer, Arthur L.
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LYMPHOID tissue , *CANCER - Abstract
Reports that dysregulation of signal transducers and activators of transcription (STAT)-responsive genes may underlie the inflammatory disease in BCL-6-deficient mice and participate in lymphoid malignancies. Development of myocarditis and pulmonary vasculitis in mice with a disrupted BCL-6 gene.
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- 1997
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5. Targeted checkpoint control of B cells undergoing positive selection in germinal centers by follicular regulatory T cells.
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Fang Ke, Benet, Zachary L., Shelyakin, Pavel, Britanova, Olga V., Gupta, Neetu, Dent, Alexander L., Moore, Bethany B., and Grigorova, Irina L.
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REGULATORY T cells , *B cells , *GERMINAL centers , *MACROPHAGE inflammatory proteins , *NUCLEAR proteins - Abstract
Follicular regulatory T cells (Tfr) can play opposite roles in the regulation of germinal center (GC) responses. Depending on the studies, Tfr suppress or support GC and B cell affinity maturation. However, which factors determine positive vs. negative effects of Tfr on the GC B cell is unclear. In this study, we show that GC centrocytes that express MYC up-regulate expression of CCL3 chemokine that is needed for both the positive and negative regulation of GC B cells by Tfr. B cell-intrinsic expression of CCL3 contributes to Tfr-dependent positive selection of foreign Ag-specific GC B cells. At the same time, expression of CCL3 is critical for direct Tfr-mediated suppression of GC B cells that acquire cognate to Tfr nuclear proteins. Our study suggests that CCR5 and CCR1 receptors promote Tfr migration to CCL3 and highlights Ccr5 expression on the Tfr subset that expresses Il10. Based on our findings and previous studies, we suggest a model of chemotactically targeted checkpoint control of B cells undergoing positive selection in GCs by Tfr, where Tfr directly probe and license foreign antigen-specific B cells to complete their positive selection in GCs but, at the same time, suppress GC B cells that present self-antigens cognate to Tfr. [ABSTRACT FROM AUTHOR]
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- 2024
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6. It takes CK2 to suppress TH2.
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Sawant, Deepali V and Dent, Alexander L
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SERINE/THREONINE kinases , *IMMUNOSUPPRESSION , *TH2 cells , *GENE expression , *CELLULAR immunity , *CELLULAR signal transduction , *ANTI-inflammatory agents , *CELLULAR control mechanisms - Published
- 2015
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7. Interactions between B cells and T follicular regulatory cells enhance susceptibility to Brucella infection independent of the anti-Brucella humoral response.
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Dadelahi, Alexis S., Abushahba, Mostafa F. N., Ponzilacqua-Silva, Bárbara, Chambers, Catherine A., Moley, Charles R., Lacey, Carolyn A., Dent, Alexander L., and Skyberg, Jerod
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B cells , *REGULATORY T cells , *HUMORAL immunity , *BRUCELLA , *OVARIAN follicle , *B cell receptors , *T cells , *ANTIGEN presentation - Abstract
Brucellosis, caused by facultative, intracellular Brucella spp., often results in chronic and/or lifelong infection. Therefore, Brucella must employ mechanisms to subvert adaptive immunity to cause chronic infection. B lymphocytes enhance susceptibility to infection with Brucella spp. though the mechanisms remain unclear. Here we investigated the role of antibody secretion, B cell receptor (BCR) specificity, and B cell antigen presentation on susceptibility to B. melitensis. We report that mice unable to secrete antibody do not display altered resistance to Brucella. However, animals with B cells that are unable to recognize Brucella through their BCR are resistant to infection. In addition, B cell MHCII expression enhances susceptibility to infection in a CD4+ T cell-dependent manner, and we found that follicular B cells are sufficient to inhibit CD4+ T cell-mediated immunity against Brucella. B cells promote development of T follicular helper (TFH) and T follicular regulatory (TFR) cells during Brucella infection. Inhibition of B cell and CD4+ T cell interaction via CD40L blockade enhances resistance to Brucella in a B cell dependent manner concomitant with suppression of TFH and TFR differentiation. Conversely, PD-1 blockade increases Brucella burdens in a B and CD4+ T cell dependent manner while augmenting T regulatory (TReg) and TFR responses. Intriguingly, TFR deficiency enhances resistance to Brucella via a B cell dependent, but antibody independent mechanism. Collectively, these results demonstrate B cells support TFR responses that promote susceptibility to Brucella infection independent of the antibody response. Author summary: Brucella can cause a life-long infection in humans, mice and livestock making it an ideal organism for investigating the mechanisms that pathogens employ to subvert host immunity and cause chronic infection. Here, we determined how B cell effector functions enhance susceptibility to Brucella. We found that animals with B cells that are unable to recognize Brucella through their BCR are resistant to infection. We also found that B cells alter the function of CD4+ T cells during Brucella infection in a MHCII- and CD40:CD40L-dependent manner. Moreover, we show that B cells promote development of T follicular regulatory cells that in turn enhance susceptibility to Brucella in an antibody independent manner. This was of particular interest, because to our knowledge, an antibody independent function of T follicular regulatory cells in modulating susceptibility to infection has not been previously reported. Collectively, this study highlights mechanisms by which Brucella infection subverts B and CD4+ T cell interactions to promote host susceptibility to infection. [ABSTRACT FROM AUTHOR]
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- 2023
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8. Lipids-?-Us: peroxisome generation of iNKT ligands.
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Brutkiewicz, Randy R and Dent, Alexander L
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LIPIDS , *KILLER cells , *PEROXISOMES , *LIGANDS (Biochemistry) , *T cells , *PHOSPHOLIPIDS , *CELL populations - Published
- 2012
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9. Germinal center B cells that acquire nuclear proteins are specifically suppressed by follicular regulatory T cells.
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Fang Ke, Benet, Zachary L., Maz, Mitra P., Jianhua Liu, Dent, Alexander L., Kahlenberg, Joanne Michelle, and Grigorova, Irina L.
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B cells , *REGULATORY T cells , *NUCLEAR proteins , *GERMINAL centers , *HUMORAL immunity , *OVARIAN follicle , *T cell receptors - Abstract
Follicular regulatory T cells (Tfr) restrict development of autoantibodies and autoimmunity while supporting high-affinity foreign antigen-specific humoral response. However, whether Tfr can directly repress germinal center (GC) B cells that acquire autoantigens is unclear. Moreover, TCR specificity of Tfr to self-antigens is not known. Our study suggests that nuclear proteins contain antigens specific to Tfr. Targeting of these proteins to antigen-specific B cells in mice triggers rapid accumulation of Tfr with immunosuppressive characteristics. Tfr then exert negative regulation of GC B cells with predominant inhibition of the nuclear protein-acquiring GC B cells, suggesting an important role of direct cognate Tfr-GC B cells interactions for the control of effector B cell response. [ABSTRACT FROM AUTHOR]
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- 2023
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10. Gut Microbiota Regulates K/BxN Autoimmune Arthritis through Follicular Helper T but Not Th17 Cells.
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Block, Katharine E., Zhong Zheng, Dent, Alexander L., Kee, Barbara L., and Haochu Huang
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ARTHRITIS , *T cells , *AUTOIMMUNE diseases , *CELL differentiation , *LABORATORY mice , *BACTERIAL communities , *JOINT diseases , *ANTIBIOTICS - Abstract
The bacterial community that colonizes mucosal surfaces helps shape the development and function of the immune system. The K/BxN autoimmune arthritis model is dependent on the microbiota, and particularly on segmented filamentous bacteria, for the autoimmune phenotype. The mechanisms of how the gut microbiota affects arthritis development are not well understood. In this study, we investigate the contribution of two T cell subsets, Thl7 and follicular helper T (Tfh), to arthritis and how microbiota modulates their differentiation. Using genetic approaches, we demonstrate that IL-17 is dispensable for arthritis. Antibiotic treatment inhibits disease in IL-17-deficient animals, suggesting that the gut microbiota regulates arthritis independent of Thl7 cells. In contrast, conditional deletion of Bcl6 in T cells blocks Tfh cell differentiation and arthritis development. Furthermore, Tfh cell differentiation is defective in antibiotic-treated mice. Taken together, we conclude that gut microbiota regulates arthritis through Tfh but not Thl7 cells. These findings have implications in our understanding of how environmental factors contribute to the development of autoimmune diseases. [ABSTRACT FROM AUTHOR]
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- 2016
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11. Deficiency of the Transcriptional Repressor B Cell Lymphoma 6 (Bcl6) Is Accompanied by Dysregulated Lipid Metabolism.
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LaPensee, Christopher R., Lin, Grace, Dent, Alexander L., and Schwartz, Jessica
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B cells , *LYMPHOMAS , *GENETIC transcription , *FAT cells , *LIPID metabolism , *METABOLIC regulation , *GENE targeting , *CELLULAR signal transduction - Abstract
The transcriptional repressor B-cell Lymphoma 6 (Bcl6) was recently identified in a profile of genes regulated in adipocytes, suggesting a relationship between Bcl6 and metabolic regulation. As a representative target gene repressed by Bcl6, Suppressor of Cytokine Signaling (Socs) 2 expression was elevated in Bcl6 deficient (KO) mice, including metabolic tissues liver, adipose tissue and muscle, as well as in spleen and thymus. Bcl6 occupied the Socs2 promoter in wild-type, but not Bcl6 KO mice, suggesting direct regulation of Socs2 by Bcl6 in vivo. Mice deficient in Bcl6 were found to exhibit multiple features of dysregulated lipid metabolism. Adipose tissue mass was dramatically reduced or absent in Bcl6 KO mice. Further, hepatic and serum triglycerides were low. Bcl6 deficiency was accompanied by decreased hepatic expression of Stearoyl-CoA desaturase 1 (Scd1) and Fatty acid synthase (Fasn) genes which encode lipogenic enzymes. Expression of the gene for the transcription factor Carbohydrate-Responsive Element Binding Protein (Chrebp), which regulates expression of lipogenic genes, was also reduced in liver of Bcl6 KO mice. Bcl6 deficiency disrupted fasting-induced increases in hepatic triglyceride deposition, but not decreases in lipogenic gene expression. Taken together, these findings suggest that in addition to its well-recognized roles in immune regulation, Bcl6 plays a role in regulatory events of lipid metabolism, and that in the absence of Bcl6, lipid metabolism in liver and adipose tissue is dysregulated. [ABSTRACT FROM AUTHOR]
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- 2014
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12. Transcriptional repressor BCL-6 immortalizes germinal center-like B cells in the absence of p53 function.
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Kusam, Saritha, Vasanwala, Farha H., and Dent, Alexander L.
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CHROMOSOMES , *ONCOGENES , *B cells , *LYMPHOMAS , *TUMOR suppressor genes - Abstract
Chromosomal rearrangements in non-Hodgkin's B-cell lymphoma implicate BCL-6 as an oncogene, yet direct evidence for BCL-6 acting as an oncogene in B cells has been lacking. Here, we show that BCL-6 can immortalize primary B cells, but only in the absence of p53 tumor suppressor function. The expression of BCL-6 led to greatly increased B-cell proliferation, particularly in response to CD40 stimulation. Furthermore, BCL-6-infected p53-deficient B cells gave rise to immortalized cell lines that could be maintained by CD40 stimulation. We found that in primary mouse B cells, BCL-6 repressed expression of the Blimp-1, p27kip1, and cyclin D2 target genes. BCL-6 did not markedly repress the PDCD2 and BCL-XL target genes. The BCL-6 immortalized cell lines had a phenotype consistent with germinal center B cells, they expressed the germinal center-specific M17 gene, and a significant fraction of the cells stained positive with PNA. Our data indicate that BCL-6 may act to maintain B cells in a germinal center-like state, and repression of Blimp-1 by BCL-6 may be particularly crucial for stabilization of the germinal center phenotype. Our data also suggest that disruption of the p53 pathway may be crucial for the development of BCL-6-expressing B-cell lymphomas.Oncogene (2004) 23, 839-844. doi:10.1038/sj.onc.1207065 [ABSTRACT FROM AUTHOR]
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- 2004
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13. IL-10-producing Tfh cells accumulate with age and link inflammation with age-related immune suppression.
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Almanan, Maha, Raynor, Jana, Ogunsulire, Ireti, Malyshkina, Anna, Mukherjee, Shibabrata, Hummel, Sarah A., Ingram, Jennifer T., Saini, Ankur, Xie, Markus M., Alenghat, Theresa, Sing Sing Way, Deepe Jr., George S., Divanovic, Senad, Singh, Harinder, Miraldi, Emily, Zajac, Allan J., Dent, Alexander L., Hölscher, Christoph, Chougnet, Claire, and Hildeman, David A.
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CELLULAR aging , *IMMUNOSUPPRESSION , *IMMUNOSENESCENCE , *T helper cells - Abstract
The article focuses on the implication of Tfh10 cells as an intriguing link between inflammaging and impaired immune responses with age. It mentions about aging results in profound immune dysfunction, resulting in the decline of vaccine responsiveness previously attributed to irreversible defects in the immune system; also focuses on declining adaptive immune function which leads to increased risk and severity of infection.
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- 2020
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14. T follicular regulatory cells and IL-10 promote food antigen-specific IgE.
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Xie, Markus M., Qiang Chen, Hong Liu, Kai Yang, Byunghee Koh, Hao Wu, Maleki, Soheila J., Hurlburt, Barry K., Cook-Mills, Joan, Kaplan, Mark H., Dent, Alexander L., Chen, Qiang, Liu, Hong, Yang, Kai, Koh, Byunghee, and Wu, Hao
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INTERLEUKINS , *RESEARCH , *IMMUNOGLOBULINS , *B cells , *ANIMAL experimentation , *RESEARCH methodology , *LYMPHOID tissue , *EVALUATION research , *MEDICAL cooperation , *CELLULAR signal transduction , *COMPARATIVE studies , *FOOD , *RESEARCH funding , *T cells , *FOOD allergy , *MICE , *ANTIGENS - Abstract
Food allergies are a major clinical problem and are driven by IgE antibodies (Abs) specific for food antigens (Ags). T follicular regulatory (Tfr) cells are a specialized subset of FOXP3+ T cells that modulate Ab responses. Here, we analyzed the role of Tfr cells in regulating Ag-specific IgE using a peanut-based food allergy model in mice. Peanut-specific IgE titers and anaphylaxis responses were significantly blunted in Tfr cell-deficient Foxp3-Cre Bcl6fl/fl mice. Loss of Tfr cells led to greatly increased nonspecific IgE levels, showing that Tfr cells have both helper and suppressor functions in IgE production in the germinal center (GC) that work together to facilitate the production of Ag-specific IgE. Foxp3-Cre Ptenfl/fl mice with augmented Tfr cell responses had markedly higher levels of peanut-specific IgE, revealing an active helper function by Tfr cells on Ag-specific IgE. The helper function of Tfr cells for IgE production involves IL-10, and the loss of IL-10 signaling by B cells led to a severely curtailed peanut-specific IgE response, decreased GCB cell survival, and loss of GC dark zone B cells after peanut sensitization. We thus reveal that Tfr cells have an unexpected helper role in promoting food allergy and may represent a target for drug development. [ABSTRACT FROM AUTHOR]
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- 2020
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15. BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection.
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Bibo Zhu, Ruixuan Zhang, Chaofan Li, Li Jiang, Min Xiang, Zhenqing Ye, Hirohito Kita, Melnick, Ari M., Dent, Alexander L., and Jie Sun
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VIRUS diseases , *INFLUENZA A virus , *NEUTROPHILS , *NATURAL immunity , *BONE marrow , *INFLAMMATION - Abstract
Neutrophils are vital for antimicrobial defense; however, their role during viral infection is less clear. Furthermore, the molecular regulation of neutrophil fate and function at the viral infected sites is largely elusive. Here we report that BCL6 deficiency in myeloid cells exhibited drastically enhanced host resistance to severe influenza A virus (IAV) infection. In contrast to the notion that BCL6 functions to suppress innate inflammation, we find that myeloid BCL6 deficiency diminished lung inflammation without affecting viral loads. Using a series of Cretransgenic, reporter, and knockout mouse lines, we demonstrate that BCL6 deficiency in neutrophils, but not in monocytes or lung macrophages, attenuated host inflammation and morbidity following IAV infection. Mechanistically, BCL6 bound to the neutrophil gene loci involved in cellular apoptosis in cells specifically at the site of infection. As such, BCL6 disruption resulted in increased expression of apoptotic genes in neutrophils in the respiratory tract, but not in the circulation or bone marrow. Consequently, BCL6 deficiency promoted tissue neutrophil apoptosis. Partial neutrophil depletion led to diminished pulmonary inflammation and decreased host morbidity. Our results reveal a previously unappreciated role of BCL6 in modulating neutrophil apoptosis at the site of infection for the regulation of host disease development following viral infection. Furthermore, our studies indicate that tissue-specific regulation of neutrophil survival modulates host inflammation and tissue immunopathology during acute respiratory viral infection. [ABSTRACT FROM AUTHOR]
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- 2019
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16. Phosphatidylinositol transfer proteins regulate megakaryocyte TGF-b1 secretion and hematopoiesis in mice.
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Capitano, Maegan, Liang Zhao, Cooper, Scott, Thorsheim, Chelsea, Suzuki, Aae, Xinxin Huang, Dent, Alexander L., Marks, Michael S., Abrams, Charles S., and Broxmeyer, Hal E.
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PHOSPHATIDYLINOSITOLS , *MEGAKARYOCYTES , *TRANSFORMING growth factors-beta , *HEMATOPOIESIS , *LABORATORY mice - Abstract
We hypothesized that megakaryocyte (MK) phosphoinositide signaling mediated by phosphatidylinositol transfer proteins (PITPs) contributes to hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) regulation. Conditional knockout mice lacking PITPs specifically in MKs and platelets (pitpα-/- and pitpα-/-/β-/-) bone marrow (BM) manifested decreased numbers of HSCs, MK-erythrocyte progenitors, and cycling HPCs. Further, pitpα-/-/β-/- BM had significantly reduced engrafting capability in competitive transplantation and limiting dilution analysis. Conditioned media (CM) from cultured pitpα-/- and pitpα-/-/β-/- BM MKs contained higher levels of transforming growth factor b1 (TGF-b1) and interleukin-4 (IL-4), among other myelosuppressive cytokines, than wildtype BM MKs. Correspondingly, BM flush fluid from pitpα-/- and pitpα-/-/β-/- mice had higher concentrations of TGF-b1. CM from pitpα-/- and pitpα-/-/β-/- MKs significantly suppressed HPC colony formation, which was completely extinguished in vitro by neutralizing anti-TGF-b antibody, and treatment of pitpα-/-/β-/- mice in vivo with anti-TGF-b antibodies completely reverted their defects in BM HSC and HPC numbers. TGF-b and IL-4 synergized to inhibit HPC colony formation in vitro. Electron microscopy analysis of pitpα-/-/β-/- MKs revealed ultrastructural defects with depleted α-granules and large, misshaped multivesicular bodies. Von Willebrand factor and thrombospondin-1, like TGF-b, are stored inMKα-granules and were also elevated in CM of cultured pitpα-/-/β-/- MKs. Altogether, these data show that ablating PITPs in MKs indirectly dysregulates hematopoiesis in the BM by disrupting α-granule physiology and secretion of TGF-β1. [ABSTRACT FROM AUTHOR]
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- 2018
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17. Paracrine IL-2 Is Required for Optimal Type 2 Effector Cytokine Production.
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Olson, Matthew R., Ulrich, Benjamin J., Hummel, Sarah A., Khan, Ibrahim, Meuris, Brice, Cherukuri, Yesesri, Dent, Alexander L., Janga, Sarath Chandra, and Kaplan, Mark H.
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PARACRINE mechanisms , *CYTOKINES , *T cells , *GOLGINS , *IN vivo studies - Abstract
IL-2 is a pleiotropic cytokine that promotes the differentiation of Th cell subsets, including Th1, Th2, and Th9 cells, but it impairs the development of Th17 and T follicular helper cells. Although IL-2 is produced by all polarized Th subsets to some level, how it impacts cytokine production when effector T cells are restimulated is unknown. We show in this article that Golgi transport inhibitors (GTIs) blocked IL-9 production. Mechanistically, GTIs blocked secretion of IL-2 that normally feeds back in a paracrine manner to promote STAT5 activation and IL-9 production. IL-2 feedback had no effect on Th1- or Th17-signature cytokine production, but it promoted Th2- and Th9-associated cytokine expression. These data suggest that the use of GTIs results in an underestimation of the presence of type 2 cytokine-secreting cells and highlight IL-2 as a critical component in optimal cytokine production by Th2 and Th9 cells in vitro and in vivo. [ABSTRACT FROM AUTHOR]
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- 2017
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18. AMP kinase promotes Bcl6 expression in both mouse and human T cells.
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Xie, Markus M., Amet, Tohti, Liu, Hong, Yu, Qigui, and Dent, Alexander L.
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BCL-6 protein , *CYCLIC-AMP-dependent protein kinase , *T cells , *GENE expression , *CELLULAR signal transduction , *LABORATORY mice - Abstract
The transcription factor Bcl6 is a master regulator of follicular helper T (T FH ) cells, and understanding the signaling pathway that induces Bcl6 and T FH cell differentiation is therefore critical. IL-2 produced during T cell activation inhibits Bcl6 expression but how T FH cells evade IL-2 inhibition is not completely understood. Here we show that Bcl6 is highly up-regulated in activated CD4 T cells following glucose deprivation (GD), and this pathway is insensitive to inhibition by IL-2. Similar to GD, the glucose analog 2-deoxyglucose (2DG) inhibits glycolysis, and 2DG induced Bcl6 expression in activated CD4 T cells. The metabolic sensor AMP kinase (AMPK) is activated when glycolysis is decreased, and the induction of Bcl6 by GD was inhibited by the AMPK antagonist compound C. Additionally, activation of AMPK by the drug AICAR caused Bcl6 up-regulation in activated CD4 T cells. When mice were immunized with KLH using AICAR as an adjuvant, there was a strong T FH –dependent enhancement of KLH-specific antibody (Ab) responses, and higher Bcl6 expression in T FH cells in vivo . Activation of AMPK strongly induced BCL6 and the up-regulation of T FH cell marker expression by human CD4 T cells. Our data reveal a major new pathway for T FH cell differentiation, conserved by both mouse and human T cells. Mature T FH cells are reported to have a lower metabolic state compared to T H 1 cells. Our data indicates that decreased metabolism may be deterministic for T FH cell differentiation, and not simply a result of T FH cell differentiation. [ABSTRACT FROM AUTHOR]
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- 2017
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19. Stat3 Is Important for Follicular Regulatory T Cell Differentiation.
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Wu, Hao, Xie, Markus M., Liu, Hong, and Dent, Alexander L.
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T cell differentiation , *IMMUNOGLOBULINS , *GERMINAL centers , *IMMUNIZATION , *ERYTHROCYTES - Abstract
The production of antibody is precisely controlled during the germinal center (GC) reaction. This process is dependent on the help from follicular T helper (Tfh) cells to germinal center (GC) B cells and is regulated by regulatory follicular T helper (Tfr) cells. How Tfr cells develop and how their suppressive activity functions are not well understood. Here, we found that Stat3 is indispensible for Tfr cell differentiation. After immunization with Sheep Red Blood Cells (SRBC), the loss of Tfr cells caused by deletion of Stat3 in Treg cells does not affect the size of Tfh or GC B cell population, but rather leads to strongly enhanced production of antigen-specific IgG1 and IgG2b. In Peyer’s patches (PPs) in the gut, we found that Stat3 expression in Treg cells is also required for Tfr cell formation to commensal organisms. However, loss of Tfr cells in the gut did not affect the numbers of Tfh cells and GC B cells, nor affect IgG1 or IgA switching by GC B cells. Overall, our study has uncovered unique roles of Stat3 in Tfr cell differentiation and the regulation of the antibody response. [ABSTRACT FROM AUTHOR]
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- 2016
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20. STAT3 Impairs STAT5 Activation in the Development of IL-9-Secreting T Cells.
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Olson, Matthew R., Verdan, Felipe Fortino, Hufford, Matthew M., Dent, Alexander L., and Kaplan, Mark H.
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STAT proteins , *T cells , *INTERLEUKIN-9 , *TRANSCRIPTION factors , *CELLULAR signal transduction , *PHYSIOLOGY - Abstract
Th cell subsets develop in response to multiple activating signals, including the cytokine environment. IL-9-secreting T cells develop in response to the combination of IL-4 and TGF-β, although they clearly require other cytokine signals, leading to the activation of transcription factors including STAT5. In Th17 cells, there is a molecular antagonism of STAT5 with STAT3 signaling, although whether this paradigm exists in other Th subsets is not clear. In this paper, we demonstrate that STAT3 attenuates the ability of STAT5 to promote the development of IL-9-secreting T cells. We demonstrate that production of IL-9 is increased in the absence of STAT3 and cytokines that result in a sustained activation of STAT3, including IL-6, have the greatest potency in repressing IL-9 production in a STAT3-dependent manner. Increased IL-9 production in the absence of STAT3 correlates with increased endogenous IL-2 production and STAT5 activation, and blocking IL-2 responses eliminates the difference in IL-9 production between wild-type and STAT3-deficient T cells. Moreover, transduction of developing Th9 cells with a constitutively active STAT5 eliminates the ability of IL-6 to reduce IL-9 production. Thus, STAT3 functions as a negative regulator of IL-9 production through attenuation of STAT5 activation and function. [ABSTRACT FROM AUTHOR]
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- 2016
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21. IFN-γ and IL-21 Double Producing T Cells Are Bcl6-Independent and Survive into the Memory Phase in Plasmodium chabaudi Infection.
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Carpio, Victor H., Opata, Michael M., Montañez, Marelle E., Banerjee, Pinaki P., Dent, Alexander L., and Stephens, Robin
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INTERLEUKIN-21 , *INTERFERONS , *PLASMODIUM , *T cells , *MALARIA , *B cells , *PHAGOCYTES - Abstract
CD4 T cells are required to fight malaria infection by promoting both phagocytic activity and B cell responses for parasite clearance. In Plasmodium chabaudi infection, one specific CD4 T cell subset generates anti-parasitic IFN-γ and the antibody-promoting cytokine, IL-21. To determine the lineage of these multifunctional T cells, we followed IFN-γ+ effector T cells (Teff) into the memory phase using Ifng-reporter mice. While Ifng+ Teff expanded, the level of the Th1 lineage-determining transcription factor T-bet only peaked briefly. Ifng+ Teff also co-express ICOS, the B cell area homing molecule CXCR5, and other Tfh lineage-associated molecules including Bcl6, the transcription factor required for germinal center (GC) T follicular helper cells (Tfh) differentiation. Because Bcl6 and T-bet co-localize to the nucleus of Ifng+ Teff, we hypothesized that Bcl6 controls the Tfh-like phenotype of Ifng+ Teff cells in P. chabaudi infection. We first transferred Bcl6-deficient T cells into wildtype hosts. Bcl6-deficient T cells did not develop into GC Tfh, but they still generated CXCR5+IFN-γ+IL-21+IL-10+ Teff, suggesting that this predominant population is not of the Tfh-lineage. IL-10 deficient mice, which have increased IFN-γ and T-bet expression, demonstrated expansion of both IFN-γ+IL-21+CXCR5+ cells and IFN-γ+ GC Tfh cells, suggesting a Th1 lineage for the former. In the memory phase, all Ifng+ T cells produced IL-21, but only a small percentage of highly proliferative Ifng+ T cells maintained a T-bethi phenotype. In chronic malaria infection, serum IFN-γ correlates with increased protection, and our observation suggests Ifng+ T cells are maintained by cellular division. In summary, we found that Ifng+ T cells are not strictly Tfh derived during malaria infection. T cells provide the host with a survival advantage when facing this well-equipped pathogen, therefore, understanding the lineage of pivotal T cell players will aid in the rational design of an effective malaria vaccine. [ABSTRACT FROM AUTHOR]
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- 2015
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22. PU.l Expression in T Follicular Helper Cells Limits CD40L-Dependent Germinal Center B Cell Development.
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Awe, Olufolakemi, Hufford, Matthew M., Hao Wu, Duy Pham, Hua-Chen Chang, Jabeen, Rukhsana, Dent, Alexander L., and Kaplan, Mark H.
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T cells , *CYTOLOGICAL research , *HEMATOPOIETIC growth factors , *IMMUNOGLOBULINS , *IMMUNOLOGY - Abstract
PU.l is an ETS family transcription factor that is important for the development of multiple hematopoietic cell lineages. Previous work demonstrated a critical role for PU.l in promoting Th9 development and in limiting Th2 cytokine production. Whether PU.l has functions in other Th lineages is not clear. In this study, we examined the effects of ectopic expression of PU.l in CD4+ T cells and observed decreased expression of genes involved with the function of T follicular helper (Tfh) cells, including 1121 and Tnfsf5 (encoding CD40U). T cells from conditional mutant mice that lack expression of PU.l in T cells (Sfpi1lck-/-) demonstrated increased production of CD40U and IL-21 in vitro. Following adjuvant-dependent or adjuvant-independent immunization, we observed that Sfpi1lck-/- mice had increased numbers of Tfh cells, increased germinal center B cells (GCB cells), and increased Ab production in vivo. This correlated with increased expression of IL-21 and CD40L in Tfh cells from Sfpi1lck-/- mice compared with control mice. Finally, although blockade of IU-21 did not affect GCB cells in Sfpillck~,~ mice, anti-CD40U treatment of immunized Sfpi1lck-/- mice decreased GCB cell numbers and Ag-specific Ig concentrations. Together, these data indicate an inhibitory role for PU.l in the function of Tfh cells, germinal centers, and Tfh-dependent humoral immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
23. Innate and Adaptive Humoral Responses Coat Distinct Commensal Bacteria with Immunoglobulin A.
- Author
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Bunker, Jeffrey J., Flynn, Theodore M., Koval, Jason C., Shaw, Dustin G., Meisel, Marlies, McDonald, Benjamin D., Ishizuka, Isabel E., Dent, Alexander L., Wilson, Patrick C., Jabri, Bana, Antonopoulos, Dionysios A., and Bendelac, Albert
- Subjects
- *
NATURAL immunity , *HUMORAL immunity , *IMMUNOGLOBULIN A , *HUMAN microbiota , *MUCOUS membranes , *CYTOMETRY - Abstract
Summary Immunoglobulin A (IgA) is prominently secreted at mucosal surfaces and coats a fraction of the intestinal microbiota. However, the commensal bacteria bound by IgA are poorly characterized and the type of humoral immunity they elicit remains elusive. We used bacterial flow cytometry coupled with 16S rRNA gene sequencing (IgA-Seq) in murine models of immunodeficiency to identify IgA-bound bacteria and elucidate mechanisms of commensal IgA targeting. We found that residence in the small intestine, rather than bacterial identity, dictated induction of specific IgA. Most commensals elicited strong T-independent (TI) responses that originated from the orphan B1b lineage and from B2 cells, but excluded natural antibacterial B1a specificities. Atypical commensals including segmented filamentous bacteria and Mucispirillum evaded TI responses but elicited T-dependent IgA. These data demonstrate exquisite targeting of distinct commensal bacteria by multiple layers of humoral immunity and reveal a specialized function of the B1b lineage in TI mucosal IgA responses. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
24. An Inhibitory Role for the Transcription Factor Stat3 in Controlling IL-4 and Bcl6 Expression in Follicular Helper T Cells.
- Author
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Hao Wu, Lin-Lin Xu, Teuscher, Paulla, Hong Liu, Kaplan, Mark H., and Dent, Alexander L.
- Subjects
- *
TRANSCRIPTION factors , *INTERLEUKIN-4 , *BCL-6 protein , *PROTEIN expression , *T helper cells , *CELL growth - Abstract
The transcription factor Bcl6 is required for development of follicular helper T (TFH) cells. Cytokines that activate Stat3 promote Bcl6 expression and TFH tell differentiation. Previous studies with an acute virus infection model showed that TFH cell differentiation was decreased but not blocked in the absence of Stat3. In this study, we further analyzed the role of Stat3 in TFH cells. In Peyer's patches, we found that compared with wild-type, Stat3-deficient TFH cells developed at a 25% lower rate and expressed increased IFN-" and IL-4. Whereas Peyer's patch germinal center B cells developed at normal numbers with Stat3-deficient TFH cells, IgGl class switching was greatly increased. Following immunization with sheep RBCs, splenic Stat3-deficient TFH cells developed at a slower rate than in control mice, and splenic germinal center B cells were markedly decreased. Stat3-deficient TFH cells developed poorly in a competitive bone marrow chimera environment. Under all conditions tested, Stat3-deficient TFH cells overexpressed both IL-4 and Bcl6, a pattern specific for the TFH, cell population. Finally, we found in vitro that repression of IL-4 expression in CD4 T cells by Bcl6 required Stat3 function. Our data indicate that Stat3 can repress the expression of Bcl6 and IL-4 in TFH cells, and that Stat3 regulates the ability of Bcl6 to repress target genes. Overall, we conclude that Stat3 is required to finetune the expression of multiple key genes in TFH cells, and that the specific immune environment determines the function of Stat3 in TFH cells. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
25. The transcriptional repressor Bcl6 controls the stability of regulatory T cells by intrinsic and extrinsic pathways.
- Author
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Sawant, Deepali V., Wu, Hao, Yao, Weiguo, Sehra, Sarita, Kaplan, Mark H., and Dent, Alexander L.
- Subjects
- *
BCL-6 protein , *GENETIC repressors , *TRANSCRIPTION factors , *HOMEOSTASIS , *FORKHEAD transcription factors , *TH2 cells , *CD25 antigen - Abstract
Foxp3+ regulatory T (Treg) cells are essential to maintain immune homeostasis, yet controversy exists about the stability of this cell population. Bcl6-deficient (Bcl6−/−) mice develop severe and spontaneous T helper type 2 (Th2) inflammation and Bcl6-deficient Treg cells are ineffective at controlling Th2 responses. We used a lineage tracing approach to analyse the fate of Treg cells in these mice. In the periphery of Bcl6−/− mice, increased numbers of Foxp3-negative 'exTreg' cells were found, particularly in the CD25+ population. ExTreg cells from Bcl6−/− mice expressed increased interleukin-17 ( IL-17) and extremely elevated levels of Th2 cytokines compared with wild-type exTreg cells. Although Treg cells normally express only low levels of cytokines, Treg cells from Bcl6−/− mice secreted higher levels of IL-4, IL-5, IL-13 and IL-17 than wild-type conventional T cells. Next, Treg-specific conditional Bcl6-deficient (Bcl6Foxp3−/−) mice were analysed. Bcl6Foxp3−/− mice do not develop inflammatory disease, indicating a requirement for non-Treg cells for inflammation in Bcl6−/− mice, and have normal numbers of exTreg cells. We induced Th2-type allergic airway inflammation in Bcl6Foxp3−/− mice, and found that while exTreg cytokine expression was normal, Bcl6-deficient Treg cells expressed higher levels of the Th2-specific regulator Gata3 than Bcl6+ Treg cells. Bcl6Foxp3−/− mice had increased numbers of Th2 cells after induction of airway inflammation and increased T cells in the bronchoalveolar lavage fluid. These data show both Treg-intrinsic and Treg-extrinsic roles for Bcl6 in controlling Treg cell stability and Th2 inflammation, and support the idea that Bcl6 expression in Treg cells is critical for controlling Th2 responses. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
26. Cytokine-Dependent Induction of CD4+ T cells with Cytotoxic Potential during Influenza Virus Infection.
- Author
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Laiqing Hua, Shuyu Yao, Pham, Duy, Li Jiang, Wright, Jeffrey, Sawant, Deepali, Dent, Alexander L., Braciale, Thomas J., Kaplan, Mark H., and Jie Sun
- Subjects
- *
CYTOKINES , *CD4 antigen , *CYTOTOXIC T cells , *INFLUENZA viruses , *PERFORINS , *GRANZYMES , *ANTIVIRAL agents , *IMMUNITY - Abstract
Recent evidence has identified the role of granzyme B- and perforin-expressing CD4+ T cells with cytotoxic potential in antiviral immunity. However, the in vivo cytokine cues and downstream pathways governing the differentiation of these cells are unclear. Here, we have identified that CD4+ T cells with cytotoxic potential are specifically induced at the site of infection during influenza virus infection. The development of CD4+ T cells with cytotoxic potential in vivo was dependent on the cooperation of the STAT2-dependent type I interferon signaling and the interleukin-2/interleukin-2 receptor alpha pathway for the induction of the transcription factors T-bet and Blimp-1. We showed that Blimp-1 promoted the binding of T-bet to the promoters of cytolytic genes in CD4+ T cells and was required for the cytolytic function of the in vitro- and in vivo-generated CD4+ T cells with cytotoxic potential. Thus, our data define the molecular basis of regulation of the in vivo development of this functionally cytotoxic Th subset during acute respiratory virus infection. The potential implications for the functions of these cells are discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
27. Insights into the Role of Bcl6 in Follicular Th Cells Using a New Conditional Mutant Mouse Model.
- Author
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Hollister, Kristin, Kusam, Saritha, Hao Wu, Ninah Clegg, Mondal, Arpita, Sawant, Deepali V., and Dent, Alexander L.
- Subjects
- *
T helper cells , *BCL genes , *T cell differentiation , *CD4 antigen , *INTERLEUKIN-10 , *PHENOTYPES , *LABORATORY mice - Abstract
The transcriptional repressor Bcl6 controls development of the follicular Th cell (TFH) lineage, but the precise mechanisms by which Bcl6 regulates this process are unclear. A model has been proposed whereby Bcl6 represses the differentiation of T cells into alternative effector lineages, thus favoring TFH cell differentiation. Analysis of T cell differentiation using Bcl6-deficient mice has been complicated by the strong proinflammatory phenotype of Bcl6-deficient myeloid cells. In this study, we report data from a novel mouse model where Bcl6 is conditionally deleted in T cells (Bcl6fl/flCreCD4 mice). After immunization, programmed death -1 (PD-1)high TFH cells in Bcl6fl/flCreCD4 mice are decreased >90% compared with control mice, and Ag-specific IgG is sharply reduced. Residual PD-1highCXCR5+ TFH cells in Bcl6fl/flCreCD4 mice show a significantly higher rate of apoptosis than do PD-1highCXCR5+ TFH cells in control mice. Immunization of Bcl6fl/flCreCD4 mice did not reveal enhanced differentiation into Th1, Th2, or Th17 lineages, although IL-10 expression by CD4 T cells was markedly elevated. Thus, T cell-extrinsic factors appear to promote the increased Th1, Th2, and Th17 responses in germline Bcl6-deficient mice. Furthermore, IL-10 may be a key target gene for Bcl6 in CD4 T cells, which enables Bcl6 to promote the TFH cell phenotype. Finally, our data reveal a novel mechanism for the role of Bcl6 in promoting TFH cell survival. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
28. The Transcription Factor Twist1 Limits T Helper 17 and T Follicular Helper Cell Development by Repressing the Gene Encoding the Interleukin-6 Receptor α Chain.
- Author
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Pham, Duy, Walline, Crystal C., Hollister, Kristin, Dent, Alexander L., Blum, Janice S., Firulli, Anthony B., and Kaplan, Mark H.
- Subjects
- *
CYTOKINE receptors , *TRANSCRIPTION factors , *GENETIC code , *INTERLEUKIN-6 receptors , *ANTIGEN-antibody reactions - Abstract
Cytokine responsiveness is a critical component of the ability of cells to respond to the extracellular milieu. Transcription factor-mediated regulation of cytokine receptor expression is a common mode of altering responses to the external environment. We identify the transcription factor Twist1 as a component of a STAT3-induced feedback loop that controls IL-6 signals by directly repressing Il6ra. Human and mouse T cells lacking Twist1 have an increased ability to differentiate into Th17 cells. Mice with a T cell-specific deletion of Twist1 demonstrate increased Th17 and T follicular helper cell development, early onset experimental autoimmune encephalomyelitis, and increased antigen-specific antibody responses. Thus, Twist1 has a critical role in limiting both cell-mediated and humoral immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
29. The Bcl6 target gene microRNA-21 promotes Th2 differentiation by a T cell intrinsic pathway
- Author
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Sawant, Deepali V., Wu, Hao, Kaplan, Mark H., and Dent, Alexander L.
- Subjects
- *
T cell differentiation , *GENE targeting , *MICRORNA , *CELLULAR signal transduction , *INFLAMMATION , *GENETIC transcription - Abstract
Abstract: The transcriptional repressor Bcl6 is a critical regulator of T helper cell fate, and inhibits Th2-type inflammation. We have found that microRNA-21 (miR-21) is a novel target gene for Bcl6 in Treg cells. Bcl6 represses and Stat3 activates miR-21 transcription through a Stat3 binding element in the promoter, indicating opposing regulation of miR-21 by the two transcription factors via the same DNA site. Ectopic expression of miR-21 promoted Th2 differentiation in non-polarized T cells. The pro-Th2 activity of miR-21 was associated with increased Gata3 expression and decreased expression of the miR-21 target gene Sprouty1. Increased miR-21 promoted Th2 and Treg gene expression in wild-type Tregs. MiR-21 could thus help promote the Th2 bias of Bcl6-deficient conventional T cells and Treg cells. MiR21 expression is increased in Th2-type inflammation, and our results define miR-21 as a critical target of Bcl6, thus providing a new link between Bcl6 and Th2 inflammation. Finally, our results reveal a novel T cell autonomous role for miR-21 in promoting Th2 differentiation. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
30. Bcl6 Controls the Th2 Inflammatory Activity of Regulatory T Cells by Repressing Gata3 Function.
- Author
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Sawant, Deepali V., Sehra, Sarita, Nguyen, Evelyn T., Jadhav, Rohit, Englert, Kate, Shinnakasu, Ryo, Giao Hangoc, Broxmeyer, Hal E., Nakayama, Toshinori, Perumal, Narayanan B., Kaplan, Mark H., and Dent, Alexander L.
- Subjects
- *
BCL-6 protein , *TH2 cells , *T cells , *GATA proteins , *CELL proliferation - Abstract
The transcriptional repressor Bcl6 is a critical arbiter of Th cell fate, promoting the follicular Th lineage while repressing other Th cell lineages. Bc16-deficient (Bcl6-/-) mice develop a spontaneous and severe Th2-type inflammatory disease, thus warranting assessment of Bc16 in regulatory T cell (Treg) function. Bcl6-/- Tregs were competent at suppressing T cell proliferation in vitro and Thi-type colitogenic T cell responses in vivo. In contrast, Bcl6-/- Tregs strongly exacerbated lung inflammation in a model of allergic airway disease and promoted higher Th2 responses, including systemic upregulation of microRNA-21. Further, Bcl6-/- Tregs were selectively impaired at controlling Th2 responses, but not Thi and Th17 responses, in mixed chimeras of Bc16-/- bone marrow with Foxp3-/- bone marrow. Bcl6-/- Tregs displayed increased levels of the Th2 transcription factor Gata3 and other Th2 and Treg genes. Bcl6 potently repressed Gata3 transcriptional transactivation, providing a mechanism for the increased expression of Th2 genes by Bcl6-/- Tregs. Gata3 has a critical role in regulating Foxp3 expression and functional fitness of Tregs; however, the signal that regulates Gata3 and restricts its transactivation of Th2 cytokines in Tregs has remained unexplored. Our results identify Bc16 as an essential transcription factor regulating Gata3 activity in Tregs. Thus, Bcl6 represents a crucial regulatory layer in the Treg functional program that is required for specific suppression of Gata3 and Th2 effector responses by Tregs. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
31. Bcl-6 and NF-κB cistromes mediate opposing regulation of the innate immune response.
- Author
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Barish, Grant D., Yu, Ruth T., Karunasiri, Malith, Ocampo, Corinne B., Dixon, Jesse, Benner, Chris, Dent, Alexander L., Tangirala, Rajendra K., and Evans, Ronald M.
- Subjects
- *
NF-kappa B , *IMMUNE response , *CHROMATIN , *ENDOTOXINS , *B cell lymphoma , *LYMPHOMAS - Abstract
In the macrophage, toll-like receptors (TLRs) are key sensors that trigger signaling cascades to activate inflammatory programs via the NF-κB gene network. However, the genomic network targeted by TLR/NF-κB activation and the molecular basis by which it is restrained to terminate activation and re-establish quiescence is poorly understood. Here, using chromatin immunoprecipitation sequencing (ChIP-seq), we define the NF-κB cistrome, which is comprised of 31,070 cis-acting binding sites responsive to lipopolysaccharide (LPS)-induced signaling. In addition, we demonstrate that the transcriptional repressor B-cell lymphoma 6 (Bcl-6) regulates nearly a third of the Tlr4-regulated transcriptome, and that 90% of the Bcl-6 cistrome is collapsed following Tlr4 activation. Bcl- 6-deficient macrophages are acutely hypersensitive to LPS and, using comparative ChIP-seq analyses, we found that the Bcl-6 and NF-κB cistromes intersect, within nucleosomal distance, at nearly half of Bcl-6-binding sites in stimulated macrophages to promote opposing epigenetic modifications of the local chromatin. These results reveal a genomic strategy for controlling the innate immune response in which repressive and inductive cistromes establish a dynamic balance between macrophage quiescence and activation via epigenetically marked cis-regulatory elements. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
32. Bcl6 and Blimp-1 Are Reciprocal and Antagonistic Regulators of T Follicular Helper Cell Differentiation.
- Author
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Johnston, Robert J., Poholek, Amanda C., DiToro, Daniel, Yusuf, Isharat, Eto, Danelle, Barnett, Burton, Dent, Alexander L., Craft, Joe, and Crotty, Shane
- Subjects
- *
T cells , *CELL differentiation , *CELLULAR immunity , *TRANSCRIPTION factors , *GENE expression , *GERMINAL centers , *B cells - Abstract
Effective B cell-mediated immunity and antibody responses often require help from CD4 T cells. It is thought that a distinct CD4+ effector T cell subset, called T follicular helper cells (TFH), provides this help; however, the molecular requirements for TFH differentiation are unknown. We found that expression of the transcription factor Bcl6 in CD4+ cells is both necessary and sufficient for in vivo TFH differentiation and T cell help to B cells in mice. In contrast, the transcription factor Bilmp-1, an antagonist of Bcl6, inhibits TFH differentiation and help, thereby preventing B cell germinal center and antibody responses. These findings demonstrate that TFH cells are required for proper B cell responses in vivo and that Bcl6 and Blimp-1 play central but opposing roles in TFH differentiation. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
33. Th1 Cells Regulate Hematopoietic Progenitor Cell Homeostasis by Production of Oncostatin M
- Author
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Broxmeyer, Hal E., Bruns, Heather A., Zhang, Shangming, Cooper, Scott, Hangoc, Giao, McKenzie, Andrew N.J., Dent, Alexander L., Schindler, Ulrike, Naeger, Lisa K., Hoey, Timothy, and Kaplan, Mark H.
- Subjects
- *
TH1 cells , *HOMEOSTASIS , *IMMUNITY - Abstract
Regulation of hematopoietic progenitor cell homeostasis is crucial for maintenance of innate immunity and the ability of the body to respond to injury and infection. In this report, we demonstrate that progenitor cell numbers and cycling status in vivo are dramatically increased in mice deficient in Stat6 and decreased in mice deficient in Stat4, targeted mutations which also alter T helper cell polarization. Experiments using mice that have T cell restricted transgenic expression of Stat4 or Stat6 or have been in vivo depleted of T cell subsets demonstrate that CD4+ T cells regulate progenitor cell activity. Injection of the Th1 cytokine Oncostatin M but not other cytokines into Stat4-deficient mice recovers progenitor cell activity to wild-type levels. Thus, T helper cells actively regulate hematopoietic progenitor cell homeostasis. [Copyright &y& Elsevier]
- Published
- 2002
- Full Text
- View/download PDF
34. BCL-6 regulates chemokine gene transcription in macrophages.
- Author
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Toney, Lisa M., Cattoretti, Giorgio, Graf, Jennifer A., Merghoub, Taha, Pandolfi, Pier-Paolo, Dalla-Favera, Riccardo, Ye, B. Hilda, and Dent, Alexander L.
- Subjects
- *
T cells , *GENETIC repressors , *INFLAMMATION , *MACROPHAGES - Abstract
The transcriptional repressor protein BCL-6, implicated in the pathogenesis of B cell lymphoma, regulates lymphocyte differentiation and inflammation. We investigated the mechanism for the T helper cell subset 2 (TH2)-type inflammation that occurs in BCL-6-/- mice. Using chimeric mice we found that the TH2-type inflammation is dependent upon nonlymphoid cells. We identified three chemokines, MCP-1, MCP-3 and MRP-1, which are negatively regulated by BCL-6 in macrophages. Promoter analysis revealed that BCL-6 is a potent repressor of MCP-1 transcription. Our results provide a mechanism for the regulation of TH2-type inflammation by BCL-6 and link TH2 differentiation to innate immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2000
- Full Text
- View/download PDF
35. Correction: IFN-γ and IL-21 Double Producing T Cells Are Bcl6-Independent and Survive into the Memory Phase in Plasmodium chabaudi Infection.
- Author
-
Carpio, Victor H., Opata, Michael M., Montañez, Marelle E., Banerjee, Pinaki P., Dent, Alexander L., and Stephens, Robin
- Subjects
- *
INTERFERONS , *INTERLEUKIN-21 , *PLASMODIUM - Published
- 2017
- Full Text
- View/download PDF
36. Correction: IFN-γ and IL-21 Double Producing T Cells Are Bcl6-Independent and Survive into the Memory Phase in Plasmodium chabaudi Infection.
- Author
-
Carpio, Victor H., Opata, Michael M., Montañez, Marelle E., Banerjee, Pinaki P., Dent, Alexander L., and Stephens, Robin
- Subjects
- *
PROTOZOAN diseases , *INTERLEUKINS , *PLASMODIUM - Published
- 2016
- Full Text
- View/download PDF
37. Aberrant Regulation of Hematopoiesis by T Cells in BAZF-Deficient Mice.
- Author
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Broxmeyer, Hal E., Sehra, Sarita, Cooper, Scott, Toney, Lisa M., Kusam, Saritha, Aloor, Jim J., Marchal, Christophe C., Dinauer, Mary C., and Dent, Alexander L.
- Subjects
- *
HEMATOPOIESIS , *T cells , *PROTEINS , *CELLS , *MICE - Abstract
The BAZF (BCL-6b) protein is highly similar to the BCL-6 transcriptional repressor. While BCL-6 has been characterized extensively, relatively little is known about the normal function of BAZF. In order to understand the physiological role of BAZF, we created BAZF-deficient mice. Unlike BCL-6-deficient mice, BAZF-deficient mice are healthy and normal in size. However, BAZF-deficient mice have a hematopoietic progenitor phenotype that is almost identical to that of BCL-6-deficient mice. Compared to wild-type mice, both BAZF-deficient and BCL-6-deficient mice have greatly reduced numbers of cycling hematopoietic progenitor cells (HPC) in the BM and greatly increased numbers of cycling HPC in the spleen. In contrast to HPC from wild-type mice, HPC from BAZF-deficient and BCL-6-deficient mice are resistant to chemokine-induced myelosuppression and do not show a synergistic growth response to granulocyte-macrophage colony-stimulating factor plus stem cell factor. Depletion of CD8 T cells in BAZF-deficient mice reverses several of the hematopoietic defects in these mice. Since both BAZF- and BCL-6-deficient mice have defects in CD8 T-cell differentiation, we hypothesize that both BCL-6 and BAZF regulate HPC homeostasis by an indirect pathway involving CD8 T cells. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
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