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Hermann, Petra M., Robert P. J. de Lange, Anton W. Pieneman, Andries ter Maat, and Rene F. Jansen. "Role of Neuropeptides Encoded on CDCH-1 Gene in the Organization of Egg-Laying Behavior in the Pond Snail, Lymnaea stagnalis." Journal of Neurophysiology 78, no. 6 (December 1, 1997): 2859–69. http://dx.doi.org/10.1152/jn.1997.78.6.2859.
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Hermann, Petra M., Robert P. J. de Lange, Anton W. Pieneman, Andries ter Maat, and Rene F. Jansen. Role of neuropeptides encoded on CDCH-1 gene in the organization of egg-laying behavior in the pond snail, Lymnaea stagnalis. J. Neurophysiol. 78: 2859–2869, 1997. Egg laying in the pond snail Lymnaea stagnalis is triggered by a discharge of the neuroendocrine caudodorsal cells (CDCs). The CDCs expresses three different caudorsal cell hormone (CDCH) genes. This gene family expresses, in total, 11 different peptides among which is the ovulation hormone. Besides the CDCs, the CDCH gene family is expressed in other central and peripheral neurons. In this study, we investigated the roles the different CDCH peptides play in the organization of egg-laying behavior. Egg-laying behavior is a sequence of stereotyped movements in which three phases can be distinguished: resting, turning, and oviposition. We have used the excitation of right pedal N (RPeN) motor neurons as a simple analogue of shell-turning behavior, one of the elements of egg-laying behavior. RPeN motor neurons were inhibited during the resting phase of egg laying but were subsequently excited at the onset of and during the turning phase. The excitatory effect could be evoked by application of beta3-CDCP on RPeN motor neurons in the CNS as well as in isolation but not by the ovulation hormone, alpha-CDCP or Calfluxin, the other CDCH-1 peptides tested. The ovulation hormone itself caused inhibition of RPeN motor neurons. Anti-CDCH–1 positive fiber tracts were found close to the cell bodies and axons of the RPeN motor neurons. Electrical stimulation of a nerve that contains these fibers resulted in excitation of the RPeN motor neurons. The effects of injection of CDCH-1 peptides into intact animals correlated well with the effects of these peptides on RPeN motor neurons. Injection of beta3-CDCP or alpha-CDCP into intact animals resulted in immediate turning behavior in the absence of egg laying itself. The ovulation hormone and Calfluxin had no immediate effect on the behavior. Furthermore, our data indicate that the individual CDCH-1 peptides act on different targets.
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Cabeza-Cabrerizo, Mar, Janneke van Blijswijk, Stephan Wienert, Daniel Heim, Robert P. Jenkins, Probir Chakravarty, Neil Rogers, et al. "Tissue clonality of dendritic cell subsets and emergency DCpoiesis revealed by multicolor fate mapping of DC progenitors." Science Immunology 4, no. 33 (March 1, 2019): eaaw1941. http://dx.doi.org/10.1126/sciimmunol.aaw1941.
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Conventional dendritic cells (cDCs) are found in all tissues and play a key role in immune surveillance. They comprise two major subsets, cDC1 and cDC2, both derived from circulating precursors of cDCs (pre-cDCs), which exited the bone marrow. We show that, in the steady-state mouse, pre-cDCs entering tissues proliferate to give rise to differentiated cDCs, which themselves have residual proliferative capacity. We use multicolor fate mapping of cDC progenitors to show that this results in clones of sister cDCs, most of which comprise a single cDC1 or cDC2 subtype, suggestive of pre-cDC commitment. Upon infection, a surge in the influx of pre-cDCs into the affected tissue dilutes clones and increases cDC numbers. Our results indicate that tissue cDCs can be organized in a patchwork of closely positioned sister cells of the same subset whose coexistence is perturbed by local infection, when the bone marrow provides additional pre-cDCs to meet increased tissue demand.
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Srinivasan, Jayashree, Bryan Helm, Zhe Su, Song Yi, Qi Liu, Ken Lau, and Lauren Ilyse Richie Ehrlich. "Cellular and molecular mediators of thymic DC homeostasis and activation." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 47.10. http://dx.doi.org/10.4049/jimmunol.208.supp.47.10.
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Abstract Central tolerance in the thymus ensures that autoreactive thymocytes undergo negative selection or diversion to the regulatory T cell (Treg) lineage. Thymic antigen presenting cells (APCs) such as medullary thymic epithelial cells (mTECs) and dendritic cells (DCs) present myriad self-peptides to thymocytes to induce central tolerance. We and others have previously shown that thymic cDCs can be subdivided into activated CCR7+MHC-IIhi and resting CCR7− MHC-IIlo cDC1 and cDC2 subsets with distinct functional properties, suggesting the thymic DC compartment may be more heterogeneous than previously described. Here, we performed single-cell RNA sequencing (scRNAseq) of hematopoietic APCs isolated from adult mouse thymi to comprehensively identify thymic DC subsets with distinct gene expression profiles. Our data reveal 11 transcriptionally distinct cDC subsets. We identify 6 cDC1 subsets, 3 cDC2 subsets, 2 activated CCR7+ “cDC3” subsets distinguished by expression of cDC1 and cDC2 markers, and 4 plasmacytoid DC clusters. Through functional assays, we find that the XCR1+ cDC3s are the most efficient at presenting mTEC-derived peptides on MHC-I and MHC-II, while 2 distinct cDC2 subsets are the most efficient at generating Tregs in vitro. Additional scRNA-seq and flow cytometry analyses of thymic DCs from mice in which thymocyte maturation was blocked at different developmental stages reveal candidate cellular and molecular crosstalk signals that regulate homeostasis and/or activation of pDC and cDC subsets. Our findings reveal hitherto unknown functional heterogeneity within the thymic DC compartment and identify potential interactions that support DC homeostasis and activation which in turn could impact central tolerance. Supported by NIH P01 AI139449-02
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Toka, Felix N., Lidia Szulc-Dąbrowska, Michal Koper, Justyna Struzik, and Malgorzata Gierynska. "Classical splenic dendritic cell subsets, cDC1 and cDC2, from C57BL/6 mice are more potent in stimulating the Th1 immune response than those from BALB/c mice during mousepox." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 140.20. http://dx.doi.org/10.4049/jimmunol.204.supp.140.20.
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Abstract Classical (conventional) dendritic cells (cDCs) specialize in presenting antigen to naïve T cells, and are divided into cDC1 (CD8α+) and cDC2 (CD11b+) subpopulations based on their lineage, surface phenotype and characteristics. Despite differences, both cDC subsets can stimulate CD4+ T cells and promote polarization toward a T helper 1 (Th1) phenotype. Many studies have shown that C57BL/6 (H-2b) and BALB/c (H-2d) mice readily mount vigorous Th1 or Th2 responses, respectively, upon infection with different infectious agents, including ectromelia virus (ECTV), responsible for mousepox in mice. In this work, we compared the ability of cDC subsets from mouse strains with different susceptibility to mousepox (C57BL/6 – resistant and BALB/c – susceptible) to stimulate the Th1 cytokine immune response during ECTV infection. Results showed that splenic cDC1 and cDC2 from BALB/c mice highly express MHC class II, CD83 and/or CD86 than those from C57BL/6 mice at 5 days post infection with ECTV. Despite higher activation status, both subsets of cDCs from BALB/c mice produce low amounts of Th1-polarizing cytokines, including IL-12 and IFN-γ, than those from C57BL/6 mice. Moreover, splenic cDC1 and cDC2 cells, from ECTV-infected C57BL/6 mice, stimulated higher proliferation and production of IFN-γ and IL-2 by allogeneic CD4+ T cells of C3H (H-2k) mice in a mixed leukocyte reaction than BALB/c mice. Both subsets of BALB/c cDCs up-regulated genes engaged in cell maturation and activation compared to C57BL/6 cDCs. Overall, our data indicate that both, cDC1 and cDC2 promote CD4+ T cell differentiation into IFN-γ-producing Th1 subset, and so ensure development of a strong cell-mediated immune response and recovery of C57BL/6 mice from mousepox.
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Audiger, Cindy, and Sylvie Lesage. "Merocytic dendritic cell: a new subset of conventional dendritic cells." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 118.11. http://dx.doi.org/10.4049/jimmunol.202.supp.118.11.
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Abstract Conventional dendritic cells (cDC) are potent antigen-presenting cells that induce the activation of naïve T cells in response to pathogens. cDC activity is mediated primarily by two cDC subsets, namely cDC1 and cDC2, each bearing unique properties. Recently, another DC subset, termed merocytic dendritic cells (mcDC), was defined. In contrast to both cDC1 and cDC2, mcDC are able to reverse T cell anergy, even in non-inflammatory conditions, properties that could be exploited to potentiate cancer treatments. Here, we further characterize mcDC to determine their relationship to cDCs. First, we demonstrate that mcDC express key cDC traits, namely they express the cDC-restricted transcription factor, Zbtb46, and are very potent inducers of mixed lymphocyte reactions. Second, transcriptomic studies reveal that mcDC are more closely related to cDC1 than to cDC2. In contrast, similar to cDC2, mcDC are dependent on IRF4, but not IRF8 and BATF3, two major transcription factors required for cDC1 differentiation. Third, investigating mcDC population dynamics in reconstitution kinetics studies and in parabiotic mice, we demonstrate that, as for cDC1 and cDC2, mcDCs are terminally differentiated cells. Altogether, these data demonstrate that mcDC compose novel cDC subset. Defining the properties of mcDC in mice may help identify a functionally equivalent subset in humans leading to the development of novel cancer immunotherapies.
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Burke, D. J., and D. Church. "Protein synthesis requirements for nuclear division, cytokinesis, and cell separation in Saccharomyces cerevisiae." Molecular and Cellular Biology 11, no. 7 (July 1991): 3691–98. http://dx.doi.org/10.1128/mcb.11.7.3691-3698.1991.
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Protein synthesis inhibitors have often been used to identify regulatory steps in cell division. We used cell division cycle mutants of the yeast Saccharomyces cerevisiae and two chemical inhibitors of translation to investigate the requirements for protein synthesis for completing landmark events after the G1 phase of the cell cycle. We show, using cdc2, cdc6, cdc7, cdc8, cdc17 (38 degrees C), and cdc21 (also named tmp1) mutants, that cells arrested in S phase complete DNA synthesis but cannot complete nuclear division if protein synthesis is inhibited. In contrast, we show, using cdc16, cdc17 (36 degrees C), cdc20, cdc23, and nocodazole treatment, that cells that arrest in the G2 stage complete nuclear division in the absence of protein synthesis. Protein synthesis is required late in the cell cycle to complete cytokinesis and cell separation. These studies show that there are requirements for protein synthesis in the cell cycle, after G1, that are restricted to two discrete intervals.
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Burke, D. J., and D. Church. "Protein synthesis requirements for nuclear division, cytokinesis, and cell separation in Saccharomyces cerevisiae." Molecular and Cellular Biology 11, no. 7 (July 1991): 3691–98. http://dx.doi.org/10.1128/mcb.11.7.3691.
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Protein synthesis inhibitors have often been used to identify regulatory steps in cell division. We used cell division cycle mutants of the yeast Saccharomyces cerevisiae and two chemical inhibitors of translation to investigate the requirements for protein synthesis for completing landmark events after the G1 phase of the cell cycle. We show, using cdc2, cdc6, cdc7, cdc8, cdc17 (38 degrees C), and cdc21 (also named tmp1) mutants, that cells arrested in S phase complete DNA synthesis but cannot complete nuclear division if protein synthesis is inhibited. In contrast, we show, using cdc16, cdc17 (36 degrees C), cdc20, cdc23, and nocodazole treatment, that cells that arrest in the G2 stage complete nuclear division in the absence of protein synthesis. Protein synthesis is required late in the cell cycle to complete cytokinesis and cell separation. These studies show that there are requirements for protein synthesis in the cell cycle, after G1, that are restricted to two discrete intervals.
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Peterson, T. A., L. Prakash, S. Prakash, M. A. Osley, and S. I. Reed. "Regulation of CDC9, the Saccharomyces cerevisiae gene that encodes DNA ligase." Molecular and Cellular Biology 5, no. 1 (January 1985): 226–35. http://dx.doi.org/10.1128/mcb.5.1.226-235.1985.
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We have cloned CDC9, the structural gene for Saccharomyces cerevisiae DNA ligase, and investigated its transcriptional regulation both as a function of cell cycle stage and after UV irradiation. The steady-state level of DNA ligase mRNA increases at least fourfold in late G1, after the completion of start but before S phase. This high level of CDC9 mRNA then decays with an apparent half-life of ca. 20 min and remains at a low basal level throughout the rest of the cell cycle. The accumulation of CDC9 mRNA in late G1 is dependent upon the completion of start but not the CDC7 and CDC8 functions. Exposure of cells to UV light elicits an eightfold increase in DNA ligase mRNA levels.
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Peterson, T. A., L. Prakash, S. Prakash, M. A. Osley, and S. I. Reed. "Regulation of CDC9, the Saccharomyces cerevisiae gene that encodes DNA ligase." Molecular and Cellular Biology 5, no. 1 (January 1985): 226–35. http://dx.doi.org/10.1128/mcb.5.1.226.
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We have cloned CDC9, the structural gene for Saccharomyces cerevisiae DNA ligase, and investigated its transcriptional regulation both as a function of cell cycle stage and after UV irradiation. The steady-state level of DNA ligase mRNA increases at least fourfold in late G1, after the completion of start but before S phase. This high level of CDC9 mRNA then decays with an apparent half-life of ca. 20 min and remains at a low basal level throughout the rest of the cell cycle. The accumulation of CDC9 mRNA in late G1 is dependent upon the completion of start but not the CDC7 and CDC8 functions. Exposure of cells to UV light elicits an eightfold increase in DNA ligase mRNA levels.
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Valdez, MD, Riccardo, William G. Finn, MD, Patricia Uherova, MD, Bertram Schnitzer, MD, and Charles W. Ross, MD. "Nodular Lymphocyte Predominant Hodgkin Lymphoma: An Immunophenotypic Reappraisal Based on a Single-Institution Experience." American Journal of Clinical Pathology 119, no. 2 (February 1, 2003): 192–98. http://dx.doi.org/10.1309/38rk-238f-cdch-5r22.
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Zhang, Shengbo, Hannah D. Coughlan, Mitra Ashayeripanah, Simona Seizova, Andrew J. Kueh, Daniel V. Brown, Wang Cao, et al. "Type 1 conventional dendritic cell fate and function are controlled by DC-SCRIPT." Science Immunology 6, no. 58 (April 2, 2021): eabf4432. http://dx.doi.org/10.1126/sciimmunol.abf4432.
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The functional diversification of dendritic cells (DCs) is a key step in establishing protective immune responses. Despite the importance of DC lineage diversity, its genetic basis is not fully understood. The transcription factor DC-SCRIPT is expressed in conventional DCs (cDCs) and their committed bone marrow progenitors but not in plasmacytoid DCs (pDCs). We show that mice lacking DC-SCRIPT displayed substantially impaired development of IRF8 (interferon regulatory factor 8)–dependent cDC1, whereas cDC2 numbers increased marginally. The residual DC-SCRIPT–deficient cDC1s had impaired capacity to capture and present cell-associated antigens and to secrete IL-12p40, two functional hallmarks of this population. Genome-wide mapping of DC-SCRIPT binding and gene expression analyses revealed a key role for DC-SCRIPT in maintaining cDC1 identity via the direct regulation of cDC1 signature genes, including Irf8. Our study reveals DC-SCRIPT to be a critical component of the gene regulatory program shaping the functional attributes of cDC1s.
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McCollum, D., M. K. Balasubramanian, L. E. Pelcher, S. M. Hemmingsen, and K. L. Gould. "Schizosaccharomyces pombe cdc4+ gene encodes a novel EF-hand protein essential for cytokinesis." Journal of Cell Biology 130, no. 3 (August 1, 1995): 651–60. http://dx.doi.org/10.1083/jcb.130.3.651.
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Schizosaccharomyces pombe cells divide by medial fission. One class of cell division mutants (cdc), the late septation mutants, defines four genes: cdc3, cdc4, cdc8, and cdc12 (Nurse, P., P. Thuriaux, and K. Nasmyth. 1976. Mol. & Gen. Genet. 146:167-178). We have cloned and characterized the cdc4 gene and show that the predicted gene product. Cdc4p, is a 141-amino acid polypeptide that is similar in sequence to EF-hand proteins including myosin light chains, calmodulin, and troponin C. Two temperature-sensitive lethal alleles, cdc4-8 and cdc4-31, accumulate multiple nuclei and multiple improper F-actin rings and septa but fail to complete cytokinesis. Deletion of cdc4 also results in a lethal terminal phenotype characterized by multinucleate, elongated cells that fail to complete cytokinesis. Sequence comparisons suggest that Cdc4p may be a member of a new class of EF-hand proteins. Cdc4p localizes to a ringlike structure in the medial region of cells undergoing cytokinesis. Thus, Cdc4p appears to be an essential component of the F-actin contractile ring. We find that Cdc4 protein forms a complex with a 200-kD protein which can be cross-linked to UTP, a property common to myosin heavy chains. Together these results suggest that Cdc4p may be a novel myosin light chain.
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Park, Sang Chul, Tae-Gyun Kim, Hyung-Ju Cho, Chang-Hoon Kim, and Joo-Heon Yoon. "Reduced BDCA3+ dendritic cells in nasal mucosa induce severe inflammation in patients with allergic rhinitis and chronic rhinosinusitis." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 147.12. http://dx.doi.org/10.4049/jimmunol.204.supp.147.12.
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Abstract Dendritic cells (DCs) are specialized antigen-presenting cells that play a crucial role in T helper (Th) cell differentiation. DCs of human airway comprise conventional DCs (cDCs) and plasmacytoid DCs (pDCs), of which the cDCs lineage consists of cDC type 1 (cDC1) and cDC type 2 (cDC2). These DCs subsets differ in ontogeny and functional properties in immune response. Thus, we aimed to evaluate the expression of different dendritic cell subsets in nasal mucosa of patients with allergic rhinitis (AR) and chronic rhinosinusitis (CRS). Nasal polyp tissues or ethmoid mucosa from patients undergoing endoscopic sinus surgery or septoplasty were collected. The expression of DCs was investigated by flow cytometry via surface markers including BDCA-1 (CD1c) for cDC1, BDCA-3 (CD141) for cDC2, and BDCA-2 (CD303) for pDC. In subjects with AR, BDCA-3+cDC levels significantly decreased in patients with accompanying CRS, more reduced in eosinophilic CRS (ECRS) than in non-eosinophilic CRS (NECRS), compared to non-CRS patients. In subjects with CRS, the expression of BDCA-3+cDC decreased in patients with accompanying AR; more reduced in multiple allergens sensitization. Consequently, the IF result showed CD4+ CD25+ Foxp3+ regulatory T cell expression was significantly decreased in CRS patients with AR compared to those without AR. Furthermore, the level of BDCA-3+cDC was also inversely related with preoperative CT scores, serum eosinophils and IgE levels. We suggest that BDCA-3+cDC may play an essential role in immunoregulation and induction of clinical tolerance. Reduced frequency of BDCA-3+cDC followed by impaired Treg expression in CRS patients with AR might reflect the mechanism of severe inflammation in patients of CRS combined with AR.
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Sanchez, M., A. Calzada, and A. Bueno. "Functionally homologous DNA replication genes in fission and budding yeast." Journal of Cell Science 112, no. 14 (July 15, 1999): 2381–90. http://dx.doi.org/10.1242/jcs.112.14.2381.
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The cdc18(+) gene of the fission yeast Schizosaccharomyces pombe is involved in the initiation of DNA replication as well as in coupling the S phase to mitosis. In this work, we show that the Saccharomyces cerevisiae CDC6 gene complements cdc18-K46 ts and cdc18 deletion mutant S. pombe strains. The budding yeast gene suppresses both the initiation and the checkpoint defects associated with the lack of cdc18(+). The Cdc6 protein interacts in vivo with Cdc2 kinase complexes. Interestingly, Cdc6 is an in vitro substrate for Cdc13/Cdc2 and Cig1/Cdc2, but not for Cig2/Cdc2-associated kinases. Overexpression of Cdc6 in fission yeast induces multiple rounds of S-phase in the absence of mitosis and cell division. This CDC6-dependent continuous DNA synthesis phenotype is independent of the presence of a functional cdc18(+) gene product and, significantly, requires only Cig2/Cdc2-associated kinase activity. Finally, these S. pombe over-replicating cells do not require any protein synthesis other than that of Cdc6. Our data strongly suggest that CDC6 and cdc18(+) are functional homologues and also support the idea that controls restricting genome duplication diverge in fission and budding yeast.
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Kovats, Susan, Sean Turner, Jinny Paul, Erola Ainsua-Enrich, and Sandra Bajana. "IRF4 and IRF8 act in CD11c+ cells to regulate terminal differentiation of lung tissue dendritic cells." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 52.6. http://dx.doi.org/10.4049/jimmunol.196.supp.52.6.
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Abstract Dendritic cells (DCs) initiate immune responses in barrier tissues including lung and skin. Conventional DC subsets, CD11b−(cDC1s) or CD11b+(cDC2s), arise via distinct networks of transcription factors involving IRF4 and IRF8 and are specialized for unique functional responses. Using mice in which a conditional Irf4 or Irf8 allele is deleted in CD11c+ cells, we determined if IRF4 or IRF8 deficiency beginning in CD11c+ cDC precursors (pre-cDCs) changed the homeostasis of mature DCs or pre-DCs in the lung, dermis and spleen. CD11c-cre-Irf4−/− mice selectively lacked a lung-resident CD11chiCD11b+SIRPa+CD24+ DC subset, but not other lung CD11b+DCs or alveolar macrophages. Numbers of CD11b+CD4+ splenic DCs, but not CD11b+ dermal DCs, were reduced, indicating cDC2s in the lung and dermis develop via different pathways. Irf4 deficiency did not alter numbers of cDC1s. CD11c-cre-Irf8−/− mice lacked lung-resident CD103+ DCs and splenic CD8a+ DCs, yet harbored increased IRF4-dependent DCs. This correlated with a reduced number of Irf8−/− pre-cDCs, which contained elevated IRF4, suggesting that Irf8 deficiency diverts pre-cDC fate. Analyses of Irf4 and Irf8 haploinsufficient mice showed that while one Irf4 allele was sufficient for lung cDC2 development, two functional Irf8 alleles were required for differentiation of lung cDC1s. Thus, IRF8 and IRF4 act in pre-cDCs to direct the terminal differentiation of cDC1 and cDC2 subsets in the lung and spleen. These data suggest that variation in IRF4 or IRF8 levels resulting from genetic polymorphisms or environmental cues will govern tissue DC numbers and therefore regulate the magnitude of DC functional responses.
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Hermann, P., A. Maat, and R. Jansen. "THE NEURAL CONTROL OF EGG-LAYING BEHAVIOUR IN THE POND SNAIL LYMNAEA STAGNALIS: MOTOR CONTROL OF SHELL TURNING." Journal of Experimental Biology 197, no. 1 (December 1, 1994): 79–99. http://dx.doi.org/10.1242/jeb.197.1.79.
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Behavioural and neurophysiological techniques were used to study the neuronal control of shell turning during egg-laying in the pond snail Lymnaea stagnalis. Egg-laying consists of three phases: resting, turning and oviposition, and is triggered by an electrical discharge in a group of neuroendocrine cells, the caudodorsal cells. During the discharge, several peptides encoded on two CDCH genes are known to be released. Behavioural experiments in which different combinations of nerves were lesioned indicated that the inferior cervical nerves are necessary for turning behaviour to occur. The right inferior cervical nerve innervates the right dorsal longitudinal muscle and contains axons of neurones that are active just prior to, and during, shell movements in freely behaving animals. These axons are probably the axons of motor neurones. The motor neurones of the dorsal longitudinal muscle were identified in the cerebral A and pedal N clusters. We have demonstrated that there is a correlation between the state of excitability of the caudodorsal cells and the electrical activity of the pedal N motor neurones. Our results indicate that the pedal N motor neurones are involved in executing the turning phase during egg-laying.
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Kuhne, Michelle, Hamlet Chu, Christopher Clarke, Brian Carr, Manuel Baca, Magdeleine Hung, Mark Nagel, Alexandre Ambrogelly, and Nishanathan Rajakumaraswamy. "847 Pharmacokinetics and pharmacodynamics of GS-3583 in cynomolgus monkeys." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A888. http://dx.doi.org/10.1136/jitc-2021-sitc2021.847.
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BackgroundThe ligand for the receptor tyrosine kinase FMS-like tyrosine kinase 3 (FLT3) plays an importantrole in hematopoiesis. FLT3 signaling is required for the differentiation andexpansion of dendritic cells. In the context of cancer immunity, the conventional dendritic cellsubtype 1 (cDC1) are required for the generation of tumor-specific T cell responses in mousepreclinical models. In human tumors cDC1 are often underrepresented in thetumor microenvironment, supporting the hypothesis that therapeutically increasing their number via FLT3 pathway stimulation has the potential to promote T cell-mediated anti-tumor activity.MethodsGS-3583 is a fusion protein composed of the extracellular domain of human FLT3 ligand(FLT3L) combined with a modified fragment crystallizable (Fc) region of human IgG4. GS-3583was designed to induce cDC1 expansion and subsequently promote tumor-reactive T cell priming, activation and recruitment into the tumor microenvironment. The pharmacokinetics (PK) and pharmacodynamics (PD) of GS-3583 has been characterized in a 4-week repeat dose GLP study in cynomolgus monkeys at doses ranging from 0.3 to 10mg/kg GS-3583 was given as an intravenous injection.ResultsImmunophenotyping analysis of peripheral blood cells from GS-3583 treated monkeys demonstrated a non-dose-dependent expansion of cDC1 and cDC2 populations. The peak expansion for cDC1 and cDC2 occurred at Day 8 to Day 15. At peak, there was a 160-fold relative increase in cDC1 and 150-fold increase in cDC2 at the highest dose tested. There were dose-dependent increases in the exposure (AUC and Cmax) of GS-3583. GS-3583 was well-tolerated with no mortality or adverse clinical signs.ConclusionsThe administration of GS-3583 leads to increases in cDC1 and cDC2 populations. It was well tolerated at the maximal dose tested with no adverse clinical signs. Further clinical development of GS-3583 is warranted.
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Silva-Sanchez, Aaron, Selene Meza-Perez, Sara L. Stone, and Troy Randall. "Sterile-activated cDC1 cells in neonatal lung induce T cell IL-4 production and lymph node maturation." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 153.16. http://dx.doi.org/10.4049/jimmunol.198.supp.153.16.
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Abstract Neonates are susceptible to respiratory tract infections, possibly due to immature pulmonary dendritic cells (cDCs). Here we assessed the development and function of conventional DCs in the lung and the lung-draining mediastinal lymph node (MedLN). We found that neonatal lungs, from days 3 to 10 of life, contained a higher proportion of CD103+ cDC1 cells than adult lungs and that these cells could be divided into a small population of CD103hi cDC1 and a larger population of CD103int cDC1, which were not found in adult lungs. A similar expansion of cDC1 cells was observed in the MedLN migratory cDCs during the first 2 weeks after birth. Transcriptional and functional assays showed that neonatal CD103int cDC1 cells had an activated phenotype and efficiently migrated to the MedLN, their formation was dependent on the transcription factor Batf3 but CD103int cDC1 cells developed independently of the microbiota or MyD88 signaling. Neonatal cDC1 cells express high levels of OX-40L and produce IL-12p40, but not IL-12p70, and stimulated the differentiation of IL-4-producing OT-II cells. Importantly, the MedLNs of neonatal Batf3−/− had poorly developed HEVs and FRCs, which were restored by transfer of neonatal lung CD103int into Batf3−/− mice. These changes were not observed following transfer of CD103hi or CCR7−/− CD103int DCs. Overall our results indicate that neonatal lung CD103int cDCs are activated as part of a developmental program that promotes MedLN maturation and biases CD4 T cell activation towards IL-4 production.
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Liu, Tiantian, Sunkyung Kim, Pritesh Desai, Do-Hyun Kim, Xiao Huang, Stephen T. Ferris, Renee Wu, et al. "Ablation of cDC2 lineage specification by mutations within the −165 kb Zeb2 enhancer." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 47.09. http://dx.doi.org/10.4049/jimmunol.208.supp.47.09.
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Abstract Efforts to determine the unique functions of the two types of classical dendritic cells, cDC1 and cDC2, are hindered by limited understanding of the divergence of the common dendritic cell progenitor (CDP). Some transcription factors act in commitment of already specified progenitors, such as Batf3 which stabilizes Irf8 autoactivation at the +32 kb Irf8 enhancer, but how other factors control CDP divergence remains unknown. Here, we report the transcriptional mechanism of CDP divergence and describe the first requirements for pre-cDC2 specification. Genetic epistasis analysis suggested that Nfil3 acts upstream of Id2, Batf3, and Zeb2 in cDC1 development but has not revealed its mechanism or targets. Analysis of newly generated NFIL3 reporter mice showed extremely transient NFIL3 expression during cDC1 specification. CUT&RUN and ChIP-seq analysis identified NFIL3 binding in the −165 kb Zeb2 enhancer at sites that also bind CCAAT-enhancer-binding proteins (C/EBPs). Mutation of these NFIL3/C/EBP sites by in vivo CRISPR/Cas9 targeting revealed functional redundancy, with C/EBPs and NFIL3 competing in binding these sites to support or repress Zeb2 expression, respectively. Mutation of these three NFIL3/C/EBP sites eliminated Zeb2 expression in myeloid, but not lymphoid progenitors, producing mice that completely lacked pre-cDC2 specification and mature cDC2 in vivo. These mice failed to make an appropriate TH2 response against H. polygyrus infection, consistent with cDC2 supporting TH2 responses to helminths. Notably, Zeb2 expression is not required to maintain cDC2 identity, but acts only to block cDC1 specification. Thus, the competition between C/EBPs and NFIL3 binding at the −165 kb Zeb2 enhancer determines CDP divergence.
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Guha, June, Byunghyun Kang, Estefania Claudio, Neelam R. Redekar, Hongshan Wang, Brian L. Kelsall, Ulrich Siebenlist, and Philip M. Murphy. "NF kappa B regulator Bcl3 controls development and function of classical dendritic cells required for resistance to Toxoplasma gondii." PLOS Pathogens 18, no. 11 (November 1, 2022): e1010502. http://dx.doi.org/10.1371/journal.ppat.1010502.
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The atypical IκB family member Bcl3 associates with p50/NF-κB1 or p52/NF-κB2 homodimers in the nucleus, and positively or negatively modulates transcription in a context-dependent manner. In mice lacking Bcl3 globally or specifically in CD11c+ cells, we previously reported that Toxoplasma gondii infection is uniformly fatal and is associated with an impaired Th1 immune response. Since Bcl3 expression in dendritic cells (DC) is pivotal for antigen presentation and since classical DCs (cDC) are major antigen presenting cells, we investigated the role of Bcl3 specifically in cDCs in vivo by crossing Zbtb46 cre mice with Bcl3flx/flx mice. Bcl3flx/flx Zbtb46 cre mice were as susceptible to lethal T. gondii infection as total Bcl3-/- mice and generated poor Th1 immune responses. Consistent with this, compared to wildtype controls, splenic Xcr1+ Bcl3-deficient cDC1 cells were defective in presenting Ova antigen to OT-I cells both for Ova257-264 peptide and after infection with Ovalbumin-expressing T. gondii. Moreover, splenic CD4+ and CD8+ T cells from infected Bcl3flx/flx Zbtb46 cre mice exhibited decreased T. gondii-specific priming as revealed by both reduced cytokine production and reduced T. gondii-specific tetramer staining. In vitro differentiation of cDCs from bone marrow progenitors also revealed Bcl3-dependent cDC-specific antigen-presentation activity. Consistent with this, splenocyte single cell RNA seq (scRNAseq) in infected mice revealed Bcl3-dependent expression of genes involved in antigen processing in cDCs. We also identified by scRNAseq, a unique Bcl3-dependent hybrid subpopulation of Zbtb46+ DCs co-expressing the monocyte/macrophage transcription factor Lysozyme M. This subpopulation exhibited Bcl3-dependent expansion after infection. Likewise, by flow cytometry we identified two T. gondii-induced hybrid subpopulations of Bcl3-dependent cDC1 and cDC2 cells both expressing monocyte/macrophage markers, designated as icDC1 and icDC2. Together, our results indicate that Bcl3 in classical DCs is a major determinant of protective T cell responses and survival in T. gondii-infection.
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Lau, Colleen M., Ioanna Tiniakou, Oriana A. Perez, Margaret E. Kirkling, George S. Yap, Hanno Hock, and Boris Reizis. "Transcription factor Etv6 regulates functional differentiation of cross-presenting classical dendritic cells." Journal of Experimental Medicine 215, no. 9 (August 7, 2018): 2265–78. http://dx.doi.org/10.1084/jem.20172323.
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An IRF8-dependent subset of conventional dendritic cells (cDCs), termed cDC1, effectively cross-primes CD8+ T cells and facilitates tumor-specific T cell responses. Etv6 is an ETS family transcription factor that controls hematopoietic stem and progenitor cell (HSPC) function and thrombopoiesis. We report that like HSPCs, cDCs express Etv6, but not its antagonist, ETS1, whereas interferon-producing plasmacytoid dendritic cells (pDCs) express both factors. Deletion of Etv6 in the bone marrow impaired the generation of cDC1-like cells in vitro and abolished the expression of signature marker CD8α on cDC1 in vivo. Moreover, Etv6-deficient primary cDC1 showed a partial reduction of cDC-specific and cDC1-specific gene expression and chromatin signatures and an aberrant up-regulation of pDC-specific signatures. Accordingly, DC-specific Etv6 deletion impaired CD8+ T cell cross-priming and the generation of tumor antigen–specific CD8+ T cells. Thus, Etv6 optimizes the resolution of cDC1 and pDC expression programs and the functional fitness of cDC1, thereby facilitating T cell cross-priming and tumor-specific responses.
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Al-Zain, Amr, Lea Schroeder, Alina Sheglov, and Amy E. Ikui. "Cdc6 degradation requires phosphodegron created by GSK-3 and Cdk1 for SCFCdc4 recognition in Saccharomyces cerevisiae." Molecular Biology of the Cell 26, no. 14 (July 5, 2015): 2609–19. http://dx.doi.org/10.1091/mbc.e14-07-1213.
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To ensure genome integrity, DNA replication takes place only once per cell cycle and is tightly controlled by cyclin-dependent kinase (Cdk1). Cdc6p is part of the prereplicative complex, which is essential for DNA replication. Cdc6 is phosphorylated by cyclin-Cdk1 to promote its degradation after origin firing to prevent DNA rereplication. We previously showed that a yeast GSK-3 homologue, Mck1 kinase, promotes Cdc6 degradation in a SCFCdc4-dependent manner, therefore preventing rereplication. Here we present evidence that Mck1 directly phosphorylates a GSK-3 consensus site in the C-terminus of Cdc6. The Mck1-dependent Cdc6 phosphorylation required priming by cyclin/Cdk1 at an adjacent CDK consensus site. The sequential phosphorylation by Mck1 and Clb2/Cdk1 generated a Cdc4 E3 ubiquitin ligase–binding motif to promote Cdc6 degradation during mitosis. We further revealed that Cdc6 degradation triggered by Mck1 kinase was enhanced upon DNA damage caused by the alkylating agent methyl methanesulfonate and that the resulting degradation was mediated through Cdc4. Thus, Mck1 kinase ensures proper DNA replication, prevents DNA damage, and maintains genome integrity by inhibiting Cdc6.
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Melgoza-González, Edgar Alonso, Mónica Reséndiz-Sandoval, Diana Hinojosa-Trujillo, Sofía Hernández-Valenzuela, Melissa García-Vega, Verónica Mata-Haro, Araceli Tepale-Segura, Laura C. Bonifaz, Armando Perez-Torres, and Jesús Hernández. "Antigen Targeting of Porcine Skin DEC205+ Dendritic Cells." Vaccines 10, no. 5 (April 26, 2022): 684. http://dx.doi.org/10.3390/vaccines10050684.
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Dendritic cell (DC) targeting by DEC205+ cells effectively promotes the internalization of antigens that may trigger a specific immune response. In this study, we evaluated the ability of a recombinant antibody, anti-DEC205 (rAb ZH9F7), to trigger cellular endocytosis in subpopulations of DCs and targeted cells after intradermal injection and subsequent migration toward lymph nodes. Furthermore, the cellular immune response was evaluated in pigs after intradermal application of the antigenized rAb ZH9F7 combined with porcine circovirus type 2 cap antigen (rAb ZH9F7-Cap). We demonstrated that rAb ZH9F7 recognized conventional type 1 and 2 DCs from the blood and skin and monocytes. It promoted receptor-mediated endocytosis and migration of cDCs and moDCs toward regional lymph nodes. Intradermal application of rAb ZH9F7-Cap induced a higher frequency of IFN-γ-secreting CD4+CD8+ T lymphocytes and antibodies against Cap protein than that in the control group. In conclusion, the rAb ZH9F7-Cap system promoted the target of skin cDC1 and cDC2, provoking migration to the regional lymph nodes and inducing a Th1 response, as evidenced by the proliferation of double-positive CD4+CD8+ T cells, which correlates with an enhanced ability to target the cDC1 subset both in vitro and in vivo.
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Ferris, Stephen T., Renee Wu, Vivek Durai, Theresa L. Murphy, and Kenneth M. Murphy. "cDC1 prime and receive help from CD4 T cells to promote anti-tumor responses." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 164.21. http://dx.doi.org/10.4049/jimmunol.204.supp.164.21.
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Abstract CD4 T cells are thought to help promote anti-tumour responses by ‘licensing’ antigen presenting cells (APCs) that activate CD8 T cells. Conventional type 1 dendritic cells (cDC1s) are responsible for cross-presentation of tumour-derived antigens to CD8 T cells. Prevailing models presume that the cDC1 is licensed by CD4 T cells that are themselves activated by a distinct cDC subset, the cDC2. The recent finding that neoantigens presented by major histocompatibility complex (MHC) class II molecules can promote rejection of tumours that lack MHC class II (MHC-II) surface expression is consistent with an indirect action of CD4 T cells, such as cDC1 licensing. However, no study has directly identified the APC that primes the CD4 T cells responsible for licensing or clearly identified the target of CD4 licensing in vivo. Here, we generated cDC1-specific Cre expressing mouse strain to inactivate or induce expression of MHC-I, MHC-II, or CD40 specifically within the cDC1 lineage. Using a tumour model that relies on CD8 T cells and CD4 T cells for rejection, we discovered that priming of CD4 T cells against tumour-derived antigens, in contrast to soluble antigens, relied overwhelmingly on the cDC1 and not the cDC2. cDC1 do not simply transport antigen to lymph nodes for processing by cDC2, since lack of MHC-II expression on cDC1 prevented CD4 T cell priming. We also found that CD40 signaling not only affects licensing of cDC1 for CD8 T cell priming, but is also critical for the activation of CD4 T cells. Thus, in the setting of tumour-derived antigens, cDC1 function as an autonomous platform capable of priming both CD4 and CD8 T cells and orchestrating their cross-talk required for optimal anti-tumour immunity.
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Motegi, F., K. Nakano, and I. Mabuchi. "Molecular mechanism of myosin-II assembly at the division site in Schizosaccharomyces pombe." Journal of Cell Science 113, no. 10 (May 15, 2000): 1813–25. http://dx.doi.org/10.1242/jcs.113.10.1813.
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Schizosaccharomyces pombe cells divide by virtue of the F-actin-based contractile ring (F-actin ring). Two myosin-II heavy chains, Myo2 and Myp2/Myo3, have been localized to the F-actin ring. Here, we investigated the mechanism of myosin-II assembly at the division site in S. pombe cells. First, we showed that Cdc4, an EF-hand protein, appears to be a common myosin light chain associated with both Myo2 and Myo3. Loss of function of both Myo2 and Myo3 caused a defect in F-actin assembly at the division site, like the phenotype of cdc4 null cells. It is suggested that Myo2, Myo3 and Cdc4 function in a cooperative manner in the formation of the F-actin ring during mitosis. Next, we investigated the dynamics of myosin-II during mitosis in S. pombe cells. In early mitosis when accumulation of F-actin cables in the medial region was not yet observed, Myo2 was detected primarily as dots widely located in the medial cortex. Myo2 fibers also became visible following the appearance of the dots. The Myo2 dots and fibers then fused with each other to form a medial cortical network. Some Myo2 dots appeared to be localized with F-actin cables which are also accumulated in the medial region. Finally these structures were packed into a thin contractile ring. In mutant cells that cannot form the F-actin ring such as cdc3(ts), cdc8(ts) and cdc12(ts), Myo2 was able to accumulate as dots in the medial cortex, whereas no accumulation of Myo2 dots was detected in cdc4(ts) cells. Moreover, disruption of F-actin in the cell by applying latrunculin-A did not affect the accumulation of Myo2 dots, suggesting that F-actin is not required for their accumulation. A truncated Myo2 which lacks putative Cdc4-binding sites (Myo2dIQs) was able to rescue myo2 null cells, myo3 null cells, cdc4(ts) mutant cells and cdc4 null cells. The Myo2dIQs could assemble into a normal-shaped ring in these cells. Therefore, its assembly at the division site does not require the function of either Cdc4 or Myo3.
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Dirks, R. W., A. G. Van Dorp, J. Van Minnen, J. A. Fransen, M. Van der Ploeg, and A. K. Raap. "Electron microscopic detection of RNA sequences by non-radioactive in situ hybridization in the mollusk Lymnaea stagnalis." Journal of Histochemistry & Cytochemistry 40, no. 11 (November 1992): 1647–57. http://dx.doi.org/10.1177/40.11.1431053.
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The subcellular localization of mRNA sequences encoding neuropeptides in neuropeptidergic cells of the pond snail Lymnaea stagnalis was investigated at the electron microscopic (EM) level by non-radioactive in situ hybridization. Various classes of probes specific for 28S rRNA and for the ovulation hormone (caudodorsal cell hormone; CDCH) mRNA were labeled with biotin or digoxigenin and were detected after hybridization with gold-labeled antibodies. Hybridizations were performed on ultra-thin sections of both Lowicryl-embedded and frozen cerebral ganglia, and a comparison demonstrated that most intense hybridization signals with an acceptable preservation of morphology were obtained with ultra-thin cryosections. Addition of 0.1% glutaraldehyde to the formaldehyde fixative improved the morphology, but on Lowicryl sections this added fixative resulted in a decrease of label intensity. A variety of probes, including plasmids, PCR products, and oligonucleotides, were used and all provided good results, although the use of oligonucleotides on Lowicryl sections resulted in decreased gold labeling. The gold particles were found mainly associated with rough endoplasmic reticulum (RER) but were also observed in lysosomal structures. Finally, the in situ hybridization method presented in this study proved to be compatible with the immunocytochemical detection of the caudodorsal cell hormone, as demonstrated by double labeling experiments.
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Diener, Nathalie, Jean-Fred Fontaine, Matthias Klein, Thomas Hieronymus, Florian Wanke, Florian C. Kurschus, Andreas Ludwig, et al. "Posttranslational modifications by ADAM10 shape myeloid antigen-presenting cell homeostasis in the splenic marginal zone." Proceedings of the National Academy of Sciences 118, no. 38 (September 15, 2021): e2111234118. http://dx.doi.org/10.1073/pnas.2111234118.
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The spleen contains phenotypically and functionally distinct conventional dendritic cell (cDC) subpopulations, termed cDC1 and cDC2, which each can be divided into several smaller and less well-characterized subsets. Despite advances in understanding the complexity of cDC ontogeny by transcriptional programming, the significance of posttranslational modifications in controlling tissue-specific cDC subset immunobiology remains elusive. Here, we identified the cell-surface–expressed A-disintegrin-and-metalloproteinase 10 (ADAM10) as an essential regulator of cDC1 and cDC2 homeostasis in the splenic marginal zone (MZ). Mice with a CD11c-specific deletion of ADAM10 (ADAM10ΔCD11c) exhibited a complete loss of splenic ESAMhi cDC2A because ADAM10 regulated the commitment, differentiation, and survival of these cells. The major pathways controlled by ADAM10 in ESAMhi cDC2A are Notch, signaling pathways involved in cell proliferation and survival (e.g., mTOR, PI3K/AKT, and EIF2 signaling), and EBI2-mediated localization within the MZ. In addition, we discovered that ADAM10 is a molecular switch regulating cDC2 subset heterogeneity in the spleen, as the disappearance of ESAMhi cDC2A in ADAM10ΔCD11c mice was compensated for by the emergence of a Clec12a+ cDC2B subset closely resembling cDC2 generally found in peripheral lymph nodes. Moreover, in ADAM10ΔCD11c mice, terminal differentiation of cDC1 was abrogated, resulting in severely reduced splenic Langerin+ cDC1 numbers. Next to the disturbed splenic cDC compartment, ADAM10 deficiency on CD11c+ cells led to an increase in marginal metallophilic macrophage (MMM) numbers. In conclusion, our data identify ADAM10 as a molecular hub on both cDC and MMM regulating their transcriptional programming, turnover, homeostasis, and ability to shape the anatomical niche of the MZ.
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Miller, Hannah L., Prabhakar Sairam Andhey, Melissa K. Swiecki, Bruce A. Rosa, Konstantin Zaitsev, Alexandra-Chloe Villani, Makedonka Mitreva, et al. "Altered ratio of dendritic cell subsets in skin-draining lymph nodes promotes Th2-driven contact hypersensitivity." Proceedings of the National Academy of Sciences 118, no. 3 (January 11, 2021): e2021364118. http://dx.doi.org/10.1073/pnas.2021364118.
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Plasmacytoid dendritic cells (pDCs) specialize in the production of type I IFN (IFN-I). pDCs can be depleted in vivo by injecting diphtheria toxin (DT) in a mouse in which pDCs express a diphtheria toxin receptor (DTR) transgene driven by the human CLEC4C promoter. This promoter is enriched for binding sites for TCF4, a transcription factor that promotes pDC differentiation and expression of pDC markers, including CLEC4C. Here, we found that injection of DT in CLEC4C-DTR+mice markedly augmented Th2-dependent skin inflammation in a model of contact hypersensitivity (CHS) induced by the hapten fluorescein isothiocyanate. Unexpectedly, this biased Th2 response was independent of reduced IFN-I accompanying pDC depletion. In fact, DT treatment altered the representation of conventional dendritic cells (cDCs) in the skin-draining lymph nodes during the sensitization phase of CHS; there were fewer Th1-priming CD326+CD103+cDC1 and more Th2-priming CD11b+cDC2. Single-cell RNA-sequencing of CLEC4C-DTR+cDCs revealed that CD326+DCs, like pDCs, expressed DTR and were depleted together with pDCs by DT treatment. Since CD326+DCs did not expressTcf4, DTR expression might be driven by yet-undefined transcription factors activating the CLEC4C promoter. These results demonstrate that altered DC representation in the skin-draining lymph nodes during sensitization to allergens can cause Th2-driven CHS.
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Moon, Hyung-Geun, Seung-Jae Kim, and Gye Young Park. "Conventional DC specific CSF1R depletion represents the reduction of the alveolar cDC2 and attenuation of allergic lung inflammation." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 65.10. http://dx.doi.org/10.4049/jimmunol.204.supp.65.10.
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Abstract Dendritic cells play a key role in sensing aeroallergen and initiating Th2 immune reaction in asthma by bridging between innate and adaptive immune responses. Among the DC subtypes, conventional DC2 (cDC2) has been known to be a major player in developing allergic asthma. We recently reported that airway epithelial cell-derived CSF1 significantly promotes allergic sensitization through activating alveolar CSF1R+ cDC2 resulting in enhanced allergen-specific IgE production and subsequent Th2 immune response. This finding highlights the fundamental role of cDC2 in allergen sensitization. However, studying cDC2 has been hindered by the lack of available cDC2 specific-Cre mouse. Since CSF1R promoter activity is relatively enhanced in cDC2, we generated Zbtb46-cre;Csf1rfl/fl mice (hereafter CSF1RΔcDC) by crossbreeding cDC specific Zbtb46-cre and CSF1R flox mice. Of interest, we found that CSF1RΔcDC has a significant reduction in cDC2 population in alveolar space compared to Zbtb46-cre mice, whereas cDC1 and cDC2 in the lung and cDC1 in alveolar space were not affected in the steady state. When the mice were subjected to the allergen challenge, the number of cDC2 migrating to regional lymph node with carrying the allergen was markedly diminished in CSF1RΔcDC mice. Subsequently, the production of total and allergen-reactive IgE was blocked and allergic lung inflammation including eosinophil recruitment was attenuated in CSF1RΔcDC mice, compared to control littermate mice. These data suggest that CSF1RΔcDC mice are suitable to investigate the specific role of cDC2 in alveolar space and CSF1R+ cDC2 in alveolar space plays a key role in allergen sensitization and asthma development.
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Hermann, P. M., A. Ter Maat, A. W. Pieneman, and R. F. Jansen. "Modulation of the Electrical Activity of Motorneurons By Neuropeptides Encoded On the Cdch-Gene of the Pond Snail Lymnaea Stagnalis." Netherlands Journal of Zoology 44, no. 3-4 (1993): 200–211. http://dx.doi.org/10.1163/156854293x00340.
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Nasu, Junta, Tomofumi Uto, Tomohiro Fukaya, Hideaki Takagi, Takehito Fukui, Noriaki Miyanaga, Yotaro Nishikawa, Sho Yamasaki, Yoshihiro Yamashita, and Katsuaki Sato. "Pivotal role of the carbohydrate recognition domain in self-interaction of CLEC4A to elicit the ITIM-mediated inhibitory function in murine conventional dendritic cells in vitro." International Immunology 32, no. 10 (May 16, 2020): 673–82. http://dx.doi.org/10.1093/intimm/dxaa034.
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Abstract C-type lectin receptors (CLRs), pattern recognition receptors (PRRs) with a characteristic carbohydrate recognition domain (CRD) in the extracellular portion, mediate crucial cellular functions upon recognition of glycosylated pathogens and self-glycoproteins. CLEC4A is the only classical CLR that possesses an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM), which possibly transduces negative signals. However, how CLEC4A exerts cellular inhibition remains unclear. Here, we report that the self-interaction of CLEC4A through the CRD is required for the ITIM-mediated suppressive function in conventional dendritic cells (cDCs). Human type 2 cDCs (cDC2) and monocytes display a higher expression of CLEC4A than cDC1 and plasmacytoid DCs (pDCs) as well as B cells. The extracellular portion of CLEC4A specifically binds to a murine cDC cell line expressing CLEC4A, while its extracellular portion lacking the N-glycosylation site or the EPS motif within the CRD reduces their association. Furthermore, the deletion of the EPS motif within the CRD or ITIM in CLEC4A almost completely impairs its suppressive effect on the activation of the murine cDC cell line, whereas the absence of the N-glycosylation site within the CRD exhibits partial inhibition on their activation. On the other hand, antagonistic monoclonal antibody (mAb) to CLEC4A, which inhibits the self-interaction of CLEC4A and its downstream signaling in murine transfectants, enhances the activation of monocytes and monocyte-derived immature DCs upon stimulation with a Toll-like receptor (TLR) ligand. Thus, our findings suggest a pivotal role of the CRD in self-interaction of CLEC4A to elicit the ITIM-mediated inhibitory signal for the control of the function of cDCs.
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Bajana, Sandra Indiana, Kevin Thomas, Joni Mengarelli, and Xiao-Hong Sun. "E protein activity in DC precursors dictates the differentiation outcome of DC subsets." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 202.22. http://dx.doi.org/10.4049/jimmunol.198.supp.202.22.
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Abstract Dendritic cells (DC) comprise plasmacytoid DC (pDC) and conventional DC (cDC) subsets; the latter is further separated into type 1 (cDC1) and type 2 (cDC2). These cells play a role in initiating and modulating immune responses. Their development is controlled by a network of transcription factors including E proteins consisting of E12, E47, HEB and E2-2, which share a basic helix-loop-helix domain mediating dimerization and DNA binding. Their activity is regulated by their antagonists, Id1-4. The balance between E and Id proteins regulates the transcription of E protein target genes. While E2-2 is essential for pDC differentiation and Id2 is indispensable for cDC1 formation, little is known about how the balance between E and Id proteins controls the early steps of the commitment of common DC precursors (CDP) to the diverse DC subsets. To address this, we used a mouse model that inducibly expresses a chimeric protein, ET2, which contains the DNA binding domain of Tal1 and the transactivation domains of E47. It can compete with Id proteins to bind endogenous E proteins and restore their DNA binding activity, thus increasing net E protein activity. Our data indicated that ET2 expression inhibited the differentiation of pDC and cDC2 subsets in vivo and in vitro. In contrast, cDC1 production was slightly elevated in steady state but dramatically increased in allergic reactions. Furthermore, we detected an augmented proportion of the newly identified cDC1 precursors and decreased representation of cDC2 precursors, suggesting E proteins skew CDPs toward the cDC1 lineage. These results are consistent with reports that E proteins activate IRF8 gene transcription. Further investigation is in progress to elucidate the molecular mechanisms.
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Chang, Fred, David Drubin, and Paul Nurse. "cdc12p, a Protein Required for Cytokinesis in Fission Yeast, Is a Component of the Cell Division Ring and Interacts with Profilin." Journal of Cell Biology 137, no. 1 (April 7, 1997): 169–82. http://dx.doi.org/10.1083/jcb.137.1.169.
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As in many other eukaryotic cells, cell division in fission yeast depends on the assembly of an actin ring that circumscribes the middle of the cell. Schizosaccharomyces pombe cdc12 is an essential gene necessary for actin ring assembly and septum formation. Here we show that cdc12p is a member of a family of proteins including Drosophila diaphanous, Saccharomyces cerevisiae BNI1, and S. pombe fus1, which are involved in cytokinesis or other actin-mediated processes. Using indirect immunofluorescence, we show that cdc12p is located in the cell division ring and not in other actin structures. When overexpressed, cdc12p is located at a medial spot in interphase that anticipates the future ring site. cdc12p localization is altered in actin ring mutants. cdc8 (tropomyosin homologue), cdc3 (profilin homologue), and cdc15 mutants exhibit no specific cdc12p staining during mitosis. cdc4 mutant cells exhibit a medial cortical cdc12p spot in place of a ring. mid1 mutant cells generally exhibit a cdc12p spot with a single cdc12p strand extending in a random direction. Based on these patterns, we present a model in which ring assembly originates from a single point on the cortex and in which a molecular pathway for the functions of cytokinesis proteins is suggested. Finally, we found that cdc12 and cdc3 mutants show a syntheticlethal genetic interaction, and a proline-rich domain of cdc12p binds directly to profilin cdc3p in vitro, suggesting that one function of cdc12p in ring assembly is to bind profilin.
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Andreasen, Buch. "Consensus Conferences in Different Countries." International Journal of Technology Assessment in Health Care 4, no. 2 (April 1988): 305–8. http://dx.doi.org/10.1017/s0266462300004104.
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AbstractThe different models of consensus development conferences (CDC5) are analyzed in relation to democratic technology assessment. In some countries CDCs are mainly concerned with influencing the quality of clinical practice and thus are dominated by medical experts. In other countries, CDCs are directed towards the public and the decision makers on the political and administrative level. The Danish experience demonstrates that CDCs may be a forceful social technology with a strong potential to influence decisions about medical as well as non-medical technology
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Saito, Yasuyuki, Satomi Komori, Takenori Kotani, Yoji Murata, and Takashi Matozaki. "The Role of Type-2 Conventional Dendritic Cells in the Regulation of Tumor Immunity." Cancers 14, no. 8 (April 13, 2022): 1976. http://dx.doi.org/10.3390/cancers14081976.
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Conventional dendritic cells (cDCs) orchestrate immune responses to cancer and comprise two major subsets: type-1 cDCs (cDC1s) and type-2 cDCs (cDC2s). Compared with cDC1s, which are dedicated to the activation of CD8+ T cells, cDC2s are ontogenically and functionally heterogeneous, with their main function being the presentation of exogenous antigens to CD4+ T cells for the initiation of T helper cell differentiation. cDC1s play an important role in tumor-specific immune responses through cross-presentation of tumor-derived antigens for the priming of CD8+ T cells, whereas little is known of the role of cDC2s in tumor immunity. Recent studies have indicated that human cDC2s can be divided into at least two subsets and have implicated these cells in both anti- and pro-tumoral immune responses. Furthermore, the efficacy of cDC2-based vaccines as well as cDC2-targeted therapeutics has been demonstrated in both mouse models and human patients. Here we summarize current knowledge about the role of cDC2s in tumor immunity and address whether these cells are beneficial in the context of antitumor immune responses.
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Novoszel, Philipp, Barbara Drobits, Martin Holcmann, Cristiano De Sa Fernandes, Roland Tschismarov, Sophia Derdak, Thomas Decker, Erwin F. Wagner, and Maria Sibilia. "The AP-1 transcription factors c-Jun and JunB are essential for CD8α conventional dendritic cell identity." Cell Death & Differentiation 28, no. 8 (March 23, 2021): 2404–20. http://dx.doi.org/10.1038/s41418-021-00765-4.
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AbstractDendritic cell (DC) development is orchestrated by lineage-determining transcription factors (TFs). Although, members of the activator-protein-1 (AP-1) family, including Batf3, have been implicated in conventional (c)DC specification, the role of Jun proteins is poorly understood. Here, we identified c-Jun and JunB as essential for cDC1 fate specification and function. In mice, Jun proteins regulate extrinsic and intrinsic pathways, which control CD8α cDC1 diversification, whereas CD103 cDC1 development is unaffected. The loss of c-Jun and JunB in DC progenitors diminishes the CD8α cDC1 pool and thus confers resistance to Listeria monocytogenes infection. Their absence in CD8α cDC1 results in impaired TLR triggering and antigen cross-presentation. Both TFs are required for the maintenance of the CD8α cDC1 subset and suppression of cDC2 identity on a transcriptional and phenotypic level. Taken together, these results demonstrate the essential role of c-Jun and JunB in CD8α cDC1 diversification, function, and maintenance of their identity.
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Lopez-Girona, Antonia, Odile Mondesert, Janet Leatherwood, and Paul Russell. "Negative Regulation of Cdc18 DNA Replication Protein by Cdc2." Molecular Biology of the Cell 9, no. 1 (January 1998): 63–73. http://dx.doi.org/10.1091/mbc.9.1.63.
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Fission yeast Cdc18, a homologue of Cdc6 in budding yeast and metazoans, is periodically expressed during the S phase and required for activation of replication origins. Cdc18 overexpression induces DNA rereplication without mitosis, as does elimination of Cdc2-Cdc13 kinase during G2 phase. These findings suggest that illegitimate activation of origins may be prevented through inhibition of Cdc18 by Cdc2. Consistent with this hypothesis, we report that Cdc18 interacts with Cdc2 in association with Cdc13 and Cig2 B-type cyclins in vivo. Cdc18 is phosphorylated by the associated Cdc2 in vitro. Mutation of a single phosphorylation site, T104A, activates Cdc18 in the rereplication assay. The cdc18-K9 mutation is suppressed by a cig2 mutation, providing genetic evidence that Cdc2-Cig2 kinase inhibits Cdc18. Moreover, constitutive expression of Cig2 prevents rereplication in cells lacking Cdc13. These findings identify Cdc18 as a key target of Cdc2-Cdc13 and Cdc2-Cig2 kinases in the mechanism that limits chromosomal DNA replication to once per cell cycle.
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Hung, Li-Yin, John L. Johnson, Yingbiao Ji, David A. Christian, Karl R. Herbine, Christopher F. Pastore, and De’Broski R. Herbert. "Wnt4 controls early cDC1 commitment to suppress Type 2 immunity." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 190.44. http://dx.doi.org/10.4049/jimmunol.202.supp.190.44.
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Abstract Whether conventional dendritic cells (cDC) acquire subset identity under direction of regenerative glycoproteins is unknown. We demonstrate that Wnt4, a beta-catenin independent Wnt ligand, is necessary and sufficient for pre-cDC1 BM specification. CD11c-restricted Wnt4 deficiency reduced mature cDC1 numbers in BM, spleen, lung, and intestine and Wnt4 directly induced of pJNK activation and cDC1 commitment. CD11cCreWnt4flox/flox mice lacked IRF8/cJun complex stabilization and had increased basal numbers of cDC2, group 2 innate lymphoid cells ILC2 and increased resistance to the parasite Nippostrongylus brasiliensis compared to CD11cCre controls. These data reveal a novel role for Wnt4 in DC commitment and pathogen-specific immunity.
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Scott, Charlotte L., Bieke Soen, Liesbet Martens, Nicolas Skrypek, Wouter Saelens, Joachim Taminau, Gillian Blancke, et al. "The transcription factor Zeb2 regulates development of conventional and plasmacytoid DCs by repressing Id2." Journal of Experimental Medicine 213, no. 6 (May 16, 2016): 897–911. http://dx.doi.org/10.1084/jem.20151715.
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Plasmacytoid dendritic cells (DCs [pDCs]) develop from pre-pDCs, whereas two lineages of conventional DCs (cDCs; cDC1s and cDC2s) develop from lineage-committed pre-cDCs. Several transcription factors (TFs) have been implicated in regulating the development of pDCs (E2-2 and Id2) and cDC1s (Irf8, Id2, and Batf3); however, those required for the early commitment of pre-cDCs toward the cDC2 lineage are unknown. Here, we identify the TF zinc finger E box–binding homeobox 2 (Zeb2) to play a crucial role in regulating DC development. Zeb2 was expressed from the pre-pDC and pre-cDC stage onward and highly expressed in mature pDCs and cDC2s. Mice conditionally lacking Zeb2 in CD11c+ cells had a cell-intrinsic reduction in pDCs and cDC2s, coupled with an increase in cDC1s. Conversely, mice in which CD11c+ cells overexpressed Zeb2 displayed a reduction in cDC1s. This was accompanied by altered expression of Id2, which was up-regulated in cDC2s and pDCs from conditional knockout mice. Zeb2 chromatin immunoprecipitation analysis revealed Id2 to be a direct target of Zeb2. Thus, we conclude that Zeb2 regulates commitment to both the cDC2 and pDC lineages through repression of Id2.
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Fujita, Kohei, Svetoslav Chakarov, Tetsuro Kobayashi, Keiko Sakamoto, Benjamin Voisin, Kaibo Duan, Taneaki Nakagawa, et al. "Cell-autonomous FLT3L shedding via ADAM10 mediates conventional dendritic cell development in mouse spleen." Proceedings of the National Academy of Sciences 116, no. 29 (July 1, 2019): 14714–23. http://dx.doi.org/10.1073/pnas.1818907116.
Full textAbstract:
Conventional dendritic cells (cDCs) derive from bone marrow (BM) precursors that undergo cascades of developmental programs to terminally differentiate in peripheral tissues. Pre-cDC1s and pre-cDC2s commit in the BM to each differentiate into CD8α+/CD103+ cDC1s and CD11b+ cDC2s, respectively. Although both cDCs rely on the cytokine FLT3L during development, mechanisms that ensure cDC accessibility to FLT3L have yet to be elucidated. Here, we generated mice that lacked a disintegrin and metalloproteinase (ADAM) 10 in DCs (Itgax-cre × Adam10-fl/fl; ADAM10∆DC) and found that ADAM10 deletion markedly impacted splenic cDC2 development. Pre-cDC2s accumulated in the spleen with transcriptomic alterations that reflected their inability to differentiate and exhibited abrupt failure to survive as terminally differentiated cDC2s. Induced ADAM10 ablation also led to the reduction of terminally differentiated cDC2s, and restoration of Notch signaling, a major pathway downstream of ADAM10, only modestly rescued them. ADAM10∆DC BM failed to generate cDC2s in BM chimeric mice with or without cotransferred ADAM10-sufficient BM, indicating that cDC2 development required cell-autonomous ADAM10. We determined cDC2s to be sources of soluble FLT3L, as supported by decreased serum FLT3L concentration and the retention of membrane-bound FLT3L on cDC2 surfaces in ADAM10∆DC mice, and by demonstrating the release of soluble FLT3L by cDC2 in ex vivo culture supernatants. Through in vitro studies utilizing murine embryonic fibroblasts, we determined FLT3L to be a substrate for ADAM10. These data collectively reveal cDC2s as FLT3L sources and highlight a cell-autonomous mechanism that may enhance FLT3L accessibility for cDC2 development and survival.
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Chang, F., A. Woollard, and P. Nurse. "Isolation and characterization of fission yeast mutants defective in the assembly and placement of the contractile actin ring." Journal of Cell Science 109, no. 1 (January 1, 1996): 131–42. http://dx.doi.org/10.1242/jcs.109.1.131.
Full textAbstract:
Fission yeast cells divide by medial cleavage using an actin-based contractile ring. We have conducted a genetic screen for temperature-sensitive mutants defective in the assembly and placement of this actin ring. Six genes necessary for actin ring formation and one gene necessary for placement of the actin ring have now been identified. The genes can be further organized into different phenotypic groups, suggesting that the gene products may have different functions in actin ring formation. Mutants of cdc3 and cdc8, which encode profilin and tropomyosin respectively, display disorganized actin patches in all cells. cdc12 and cdc15 mutants display disorganized actin patches during mitosis, but normal interphase actin patterns. cdc4 and rng2 mutants display disorganized actin cables during mitosis, but normal interphase actin patterns. In mid1 mutants, the actin ring and septum are positioned at random locations and angles on the cell surface, although the nucleus is positioned normally, indicating that the mid1 gene product is required to couple the division site to the position of the nucleus. mid1 mutant cells may reveal a new cell cycle checkpoint in telophase that coordinates cell division and the proper distribution of nuclei. The actin ring forms medially in a beta-tubulin mutant, showing that actin ring formation and placement are not dependent on the mitotic spindle.
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Hernández-García, Elena, Francisco J. Cueto, Emma C. L. Cook, Ana Redondo-Urzainqui, Sara Charro-Zanca, Iñaki Robles-Vera, Ruth Conde-Garrosa, et al. "Conventional type 1 dendritic cells protect against age-related adipose tissue dysfunction and obesity." Cellular & Molecular Immunology 19, no. 2 (January 4, 2022): 260–75. http://dx.doi.org/10.1038/s41423-021-00812-7.
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AbstractConventional dendritic cells (cDCs) scan and integrate environmental cues in almost every tissue, including exogenous metabolic signals. While cDCs are critical in maintaining immune balance, their role in preserving energy homeostasis is unclear. Here, we showed that Batf3-deficient mice lacking conventional type 1 DCs (cDC1s) had increased body weight and adiposity during aging. This led to impaired energy expenditure and glucose tolerance, insulin resistance, dyslipidemia, and liver steatosis. cDC1 deficiency caused adipose tissue inflammation that was preceded by a paucity of NK1.1+ invariant NKT (iNKT) cells. Accordingly, among antigen-presenting cells, cDC1s exhibited notable induction of IFN-γ production by iNKT cells, which plays a metabolically protective role in lean adipose tissue. Flt3L treatment, which expands the dendritic cell (DC) compartment, mitigated diet-induced obesity and hyperlipidemia in a Batf3-dependent manner. This effect was partially mediated by NK1.1+ cells. These results reveal a new critical role for the cDC1-iNKT cell axis in the regulation of adipose tissue homeostasis.
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Yoon, H. J., S. Loo, and J. L. Campbell. "Regulation of Saccharomyces cerevisiae CDC7 function during the cell cycle." Molecular Biology of the Cell 4, no. 2 (February 1993): 195–208. http://dx.doi.org/10.1091/mbc.4.2.195.
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The yeast Cdc7 function is required for the G1/S transition and is dependent on passage through START, a point controlled by the Cdc28/cdc2/p34 protein kinase. CDC7 encodes a protein kinase activity, and we now show that this kinase activity varies in the cell cycle but that protein levels appear to remain constant. We present several lines of evidence that periodic activation of CDC7 kinase is at least in part through phosphorylation. First, the kinase activity of the Cdc7 protein is destroyed by dephosphorylation of the protein in vitro with phosphatase. Second, Cdc7 protein is hypophosphorylated and inactive as a kinase in extracts of cells arrested at START but becomes active and maximally phosphorylated subsequent to passage through START. The phosphorylation pattern of Cdc7 protein is complex. Phosphopeptide mapping reveals four phosphopeptides in Cdc7 prepared from asynchronous yeast cells. Both autophosphorylation and phosphorylation in trans appear to contribute to this pattern. Autophosphorylation is shown to occur by using a thermolabile Cdc7 protein. A protein in yeast extracts can phosphorylate and activate Cdc7 protein made in Escherichia coli, and phosphorylation is thermolabile in cdc28 mutant extracts. Cdc7 protein carrying a serine to alanine change in the consensus recognition site for Cdc28 kinase shows an altered phosphopeptide map, suggesting that this site is important in determining the overall Cdc7 phosphorylation pattern.
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Batich, Kristen, Ching Wen Chen, Sebastian Wellford, Kianna Dao, Annie Park Moseman, Kelly Hotchkiss, Sarah Cook, David Snyder, John Sampson, and Ashley Moseman. "IMMU-18. MIGRATION OF DENDRITIC CELLS THROUGH THE BRAIN-MENINGEAL LYMPHATIC-DRAINING LYMPH NODE NETWORK IN ORTHOTOPIC GLIOMA MODELS." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii135. http://dx.doi.org/10.1093/neuonc/noac209.516.
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Abstract INTRODUCTION Limited migration of dendritic cell (DC) vaccines to draining lymph nodes (DLN) remains a major limitation to DC efficacy for malignant gliomas. Our prior work demonstrated that increased peripheral DC migration to DLN results in enhanced antitumor efficacy. Given this, we studied DC trafficking in mouse gliomas, the meningeal lymphatic vessel (MLV) system, and the draining cervical lymph nodes (CLN). METHODS To elevate host DC populations, C57BL/6 and VMDk mice were implanted with B16-FMS-like tyrosine kinase 3 ligand (FLT3L) melanoma or with B16-FLT3L supernatant. Mice were implanted intracranially with CT2A, GL261-OVA, and SMA560 syngeneic glioma lines in the right parietal lobe. Antitumor efficacy was measured by tumor weights and median overall survival (mOS). RESULTS DC injected into glioma hemispheres display delayed kinetics of peak migration to CLN compared to control (7 days (d) vs 3d post-injection (pi), respectively). Migration of intraventricular (ivn)-injected DC to CLN is superior at days 1, 3 and 7 pi when glioma is present (p = 0.026). B16-FLT3L supernatant results in a disproportionate systemic expansion in conventional type 1 over type 2 DC (cDC1 > cDC2) compared to media control (cDC1, cDC2 fold change over media for spleen = 27,11; DLN = 6,2; blood = 6,3). Pulsed dosing of FLT3L supernatant results in significantly greater numbers of splenic cDC1 compared to daily FLT3L dosing (p = 0.002). Mice with CT2A and continuous FLT3L secretion in vivo show longer survival (mOS 30d) compared to mice with continuous GM-CSF secretion (mOS 22d) (p = 0.009). Mice with SMA560 and FLT3L secretion have significantly reduced glioma growth compared to tumor alone, GM-CSF-secreting tumors, and mixed FLT3L/GM-CSF-secreting tumors (p = 0.029). CONCLUSION FLT3L signaling in vivo results in cDC1 > cDC2 generation and migration through the CNS with more favorable glioma efficacy. Modeling of DC migration through the glioma-MLV-CLN system with FLT3L stimulation permits testing of strategies to improve DC therapy.
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Izumi, Gentaro, Keiko Nakano, Seddon Y. Thomas, Gregory Whitehead, Sara A. Grimm, Hideki Nakano, and Donald N. Cook. "Ly-6C+CD11b+conventional dendritic cells accumulate in inflamed lung and differentiate into type 2 dendritic cells." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 119.23. http://dx.doi.org/10.4049/jimmunol.202.supp.119.23.
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Abstract Allergic asthma is a complex inflammatory disease characterized by airway obstruction and airway hyperresponsiveness. Pulmonary dendritic cells are critical for allergic sensitization as they take up inhaled allergens and direct differentiation of allergen-specific helper T cell lineages in lung-draining lymph nodes. In this study, we used mass cytometry to study lung DC subsets that increase in frequency after allergen inhalation. This approach revealed a novel cell population displaying Ly-6C, in addition to surface markers routinely used to identify type 2 conventional DCs (cDC2), including CD11b and CD26. These Ly-6C+ cells had dendrites, lacked monocyte/macrophage markers such as F4/80 and CD115, and were absent in the mice lacking FMS-like tyrosine kinase 3ligand (FLT3L), a growth factor essential for cDC differentiation. Based on these observations, we conclude that this novel population represents bona fide cDCs. Their numbers in the lung were low at steady state, but increased dramatically after allergic sensitization. Cultured DC precursors (preDCs) displayed Ly-6C, but lost that marker by time. Ly-6C+CD11b+cDCs freshly isolated from mouse lung also lost Ly-6C expression after ex vivo culture. Together, these results suggest that Ly-6C+CD11b+cDCs are the precursor of cDC2. Given that the number of these DCs increase dramatically in the lung after allergen inhalation, they might play important roles in allergic sensitization and the induction of allergic asthma.
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Kitada, K., A. L. Johnson, L. H. Johnston, and A. Sugino. "A multicopy suppressor gene of the Saccharomyces cerevisiae G1 cell cycle mutant gene dbf4 encodes a protein kinase and is identified as CDC5." Molecular and Cellular Biology 13, no. 7 (July 1993): 4445–57. http://dx.doi.org/10.1128/mcb.13.7.4445-4457.1993.
Full textAbstract:
We have isolated a multicopy suppressor of the temperature-sensitive growth phenotype of organisms carrying mutations of DBF4, a gene that is required for the initiation of chromosomal DNA replication in Saccharomyces cerevisiae and that interacts with the CDC7 protein kinase. Nucleotide sequence analysis of the suppressor gene, provisionally named MSD2, revealed an open reading frame encoding a protein with a calculated M(r) of 81,024, with amino acid sequence similarity to the catalytic domains of protein kinases. Both genetic linkage and complementation analyses indicated that MSD2 is identical to the cell division cycle gene CDC5. An activity that phosphorylated exogenously added casein was immunoprecipitated by antiserum against a TrpE-Cdc5 fusion protein from lysates of wild-type cells containing CDC5 on a multicopy plasmid but not of cells bearing a small deletion in the predicted protein kinase domain of CDC5 on the plasmid. Deletion of CDC5 was lethal and resulted in a dumbbell-shaped terminal morphology, with the nuclei almost divided but still connected. Consistent with the function at the G2/M boundary, the CDC5 transcript accumulated periodically during the cell cycle, peaking at the G2/M boundary. CDC5 on a multicopy plasmid also suppresses temperature-sensitive cdc15, cdc20, and dbf2 mutations which affect mitosis during the cell cycle.
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Kitada, K., A. L. Johnson, L. H. Johnston, and A. Sugino. "A multicopy suppressor gene of the Saccharomyces cerevisiae G1 cell cycle mutant gene dbf4 encodes a protein kinase and is identified as CDC5." Molecular and Cellular Biology 13, no. 7 (July 1993): 4445–57. http://dx.doi.org/10.1128/mcb.13.7.4445.
Full textAbstract:
We have isolated a multicopy suppressor of the temperature-sensitive growth phenotype of organisms carrying mutations of DBF4, a gene that is required for the initiation of chromosomal DNA replication in Saccharomyces cerevisiae and that interacts with the CDC7 protein kinase. Nucleotide sequence analysis of the suppressor gene, provisionally named MSD2, revealed an open reading frame encoding a protein with a calculated M(r) of 81,024, with amino acid sequence similarity to the catalytic domains of protein kinases. Both genetic linkage and complementation analyses indicated that MSD2 is identical to the cell division cycle gene CDC5. An activity that phosphorylated exogenously added casein was immunoprecipitated by antiserum against a TrpE-Cdc5 fusion protein from lysates of wild-type cells containing CDC5 on a multicopy plasmid but not of cells bearing a small deletion in the predicted protein kinase domain of CDC5 on the plasmid. Deletion of CDC5 was lethal and resulted in a dumbbell-shaped terminal morphology, with the nuclei almost divided but still connected. Consistent with the function at the G2/M boundary, the CDC5 transcript accumulated periodically during the cell cycle, peaking at the G2/M boundary. CDC5 on a multicopy plasmid also suppresses temperature-sensitive cdc15, cdc20, and dbf2 mutations which affect mitosis during the cell cycle.
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Jenkins, Meagan M., Holly Bachus, Beatriz Leon-Ruiz, and Andre Ballesteros-Tato. "Trafficking of lung-migratory cDC2s into the spleen following influenza virus infection." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 102.3. http://dx.doi.org/10.4049/jimmunol.200.supp.102.3.
Full textAbstract:
Abstract Trafficking of antigen-bearing, migratory conventional dendritic cells type 1 (cDC1) and type 2 (cDC2) from the lung into the lung-draining mediastinal LN (mLN) is essential for priming T cell responses to influenza virus. In the absence of cDC1s and cDC2s, or when these are unable to traffic from the lung into the mLN, T cell responses are compromised, which highlights the importance of these DC subsets in the generation of T-cell-dependent immunity to influenza. Importantly, it is generally considered that cDCs shortly die after reaching the mLN and therefore do not recirculate back to the blood. Nevertheless, DCs purified from the spleen of intransally influenza-infected mice efficiently prime CD8+ T cell responses. Paradoxically, the two locations are not connected by the lymphatic vasculature and the intransally-administered antigens do not freely reach the blood circulation. Thus, is not clear how DCs in the spleen acquire influenza antigens following intranasal infection. Here we show that a fraction of the lung-migratory cDC2s that reach the mLN following influenza virus infection egress from the mLN, reenter the blood circulation and subsequently migrate into the spleen to prime CD8+ T cell Responses. Collectively, our results demonstrate a new paradigm of DC migration, offer new insights into how systemic T cell responses to influenza are initiated, and will ultimately reveal new strategies to elicit systemic responses to vaccination.
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Pallazola, Alexander M., Jessica X. Rao, Dawit T. Mengistu, Maria S. Morcos, Mariam S. Toma, Valerie R. Stolberg, Alexandra Tretyakova, Lisa McCloskey, Jeffrey L. Curtis, and Christine M. Freeman. "Human lung cDC1 drive increased perforin-mediated NK cytotoxicity in chronic obstructive pulmonary disease." American Journal of Physiology-Lung Cellular and Molecular Physiology 321, no. 6 (December 1, 2021): L1183—L1193. http://dx.doi.org/10.1152/ajplung.00322.2020.
Full textAbstract:
In chronic obstructive pulmonary disease (COPD), lung natural killer cells (NKs) lyse autologous lung epithelial cells in vitro, but underlying mechanisms and their relationship to epithelial cell apoptosis in vivo are undefined. Although this cytolytic capacity of lung NKs depends on priming by dendritic cells (DCs), whether priming correlates with DC maturation or is limited to a specific DC subset is also unknown. We recruited ever-smokers (≥10 pack-years; n = 96) undergoing clinically indicated lung resections. We analyzed lung NKs for cytotoxic molecule transcripts and for cytotoxicity, which we correlated with in situ detection of activated Caspase-3/7+ airway epithelial cells. To investigate DC priming, we measured lung DC expression of CCR2, CCR7, and CX3CR1 and cocultured peripheral blood NKs with autologous lung DCs, either matured using lipopolysaccharide (LPS) (nonobstructed smokers) or separated into conventional dendritic cell type-1 (cDC1) versus cDC type-2 (cDC2) (COPD). Lung NKs in COPD expressed more perforin ( P < 0.02) and granzyme B ( P < 0.03) transcripts; inhibiting perforin blocked in vitro killing by lung NKs. Cytotoxicity in vitro correlated significantly ( Sr = 0.68, P = 0.0043) with numbers of apoptotic epithelial cells per airway. In nonobstructed smokers, LPS-induced maturation enhanced DC-mediated priming of blood NKs, reflected by greater epithelial cell death. Although CCR7 expression was greater in COPD in both cDC1 ( P < 0.03) and cDC2 ( P = 0.009), only lung cDC1 primed NK killing. Thus, rather than being intrinsic to those with COPD, NK priming is a capacity of human lung DCs that is inducible by recognition of bacterial (and possibly other) danger signals and restricted to the cDC1 subset.
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O’Rourke, Allison R., and Jessica A. Hamerman. "Flightless-1 promotes lung CD103+ cDC phagocytosis and migration." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 69.14. http://dx.doi.org/10.4049/jimmunol.204.supp.69.14.
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Abstract Dendritic cells are specialized antigen-presenting cells integral for bridging the innate and adaptive immune responses. Critical to dendritic cell function is the need for a dynamic actin cytoskeleton. Flightless-1 is an actin capping protein linked to processes vital for dendritic cell immune functions including cell extension formation, phagocytosis, cell migration, and cell adhesion. Consistent with an important role in actin dynamics, whole body Flightless-1 knockouts are embryonic lethal. To enable further study of Flightless-1 in the immune response, we made mice with dendritic cell Flightless-1 deficiency using the CD11c-CRE driver. Homeostatic cDC1 and cDC2 populations in the spleen and lymph nodes were unchanged in DC-Flightless-1 knockouts relative to control animals. However, DC-Flightless-1 ablation led to a developmental disadvantage when in competition with WT DCs in mixed bone marrow chimeras. Upon LPS challenge in the airways, the Flightless-deficient cDC1 population showed reduced phagocytosis and migration to the lung draining lymph nodes. The DC migratory defect in the absence of Flightless-1 was supported by decreased CCR7 expression in both cDC1 and cDC2 populations. We hypothesize that the observed defects in phagocytosis and migration in Flightless-1-deficient dendritic cells are due to an altered actin cytoskeleton, which may also affect other actin-based immune structures. Current experiments are testing this hypothesis, and investigating the ability of Flightless-deficient DC to prime T cell responses.