scholarly journals Exhausted mature dendritic cells exhibit a slower and less persistent random motility but retain chemotaxis against CCL19

2021 ◽  
Author(s):  
Yongjun Choi ◽  
Vijaya Sunkara ◽  
Yeojin Lee ◽  
Yoon-Kyoung Cho
Keyword(s):  
Dendritic Cells ◽  
Space Exploration ◽  
Cellular Migration ◽  
Migration Behavior ◽  
Cellular Motility ◽  
Random Motility ◽  
Peripheral Tissues ◽  
Inflammatory Conditions ◽  
Effective Immune Response ◽  
Speed Fluctuation

Dendritic cells (DCs), which are immune sentinels in the peripheral tissues, play a number of roles, including patrolling for pathogens, internalising antigens, transporting antigens to the lymph nodes (LNs), interacting with T cells, and secreting cytokines. The well-coordinated migration of DCs under various immunological or inflammatory conditions is therefore essential to ensure an effective immune response. Upon maturation, DCs migrate faster and more persistently than immature DCs (iDCs), which is believed to facilitate CCR7-dependent chemotaxis. It has been reported that lipopolysaccharide-activated DCs produce IL-12 only transiently, and become resistant to further stimulation through exhaustion. However, little is known about the influence of DC exhaustion on cellular motility. Here, we studied the cellular migration of exhausted DCs in tissue-mimicked confined environments. We found that the speed of exhausted matured DCs (xmDCs) decreased significantly compared to active matured DCs (amDCs) and iDCs. In contrast, the speed fluctuation increased compared to that of amDCs and was similar to that of iDCs. In addition, the diffusivity of the xmDCs was significantly lower than that of the amDCs, which implies that DC exhaustion reduces the space exploration ability. Interestingly, CCR7-dependent chemotaxis against CCL19 in xmDCs was not considerably different from that observed in amDCs. Taken together, we report a unique intrinsic cell migration behavior of xmDCs, which exhibit a slower, less persistent, and less diffusive random motility, which results in the DCs remaining at the site of infection, although a well-preserved CCR7-dependent chemotactic motility is maintained.

scholarly journals Exhausted mature dendritic cells exhibit a slower and less persistent random motility but retain chemotaxis against CCL19

Lab on a Chip ◽  
2022 ◽  
Author(s):  
Yong-jun Choi ◽  
Vijaya Sunkara ◽  
Yeojin Lee ◽  
Yoon-Kyoung Cho
Keyword(s):  
Dendritic Cells ◽  
Lymph Nodes ◽  
Random Motility ◽  
Peripheral Tissues

Dendritic cells (DCs), which are immune sentinels in the peripheral tissues, play a number of roles, including patrolling for pathogens, internalising antigens, transporting antigens to the lymph nodes (LNs), interacting...

scholarly journals Modulation of Cellular Migration and Survival by c-Myc through the Downregulation of Urokinase (uPA) and uPA Receptor

2010 ◽  
Vol 30 (7) ◽  
pp. 1838-1851 ◽  
Author(s):  
Daniela Alfano ◽  
Giuseppina Votta ◽  
Almut Schulze ◽  
Julian Downward ◽  
Mario Caputi ◽  
...  
Keyword(s):  
Cell Motility ◽  
Cellular Transformation ◽  
Tumor Formation ◽  
Cellular Migration ◽  
Epithelial Cell Line ◽  
Cellular Motility ◽  
Upa Receptor ◽  
Upar Expression ◽  
Repressive Effect ◽  
Cell Invasiveness

ABSTRACT It has been proposed that c-Myc proapoptotic activity accounts for most of its restraint of tumor formation. We established a telomerase-immortalized human epithelial cell line expressing an activatable c-Myc protein. We found that c-Myc activation induces, in addition to increased sensitivity to apoptosis, reductions in cell motility and invasiveness. Transcriptome analysis revealed that urokinase (uPA) and uPA receptor (uPAR) were strongly downregulated by c-Myc. Evidence is provided that the repression of uPA and uPAR may account for most of the antimigratory and proapoptotic activities of c-Myc. c-Myc is known to cooperate with Ras in cellular transformation. We therefore investigated if this cooperation could converge in the control of uPA/uPAR expression. We found that Ras is able to block the effects of c-Myc activation on apoptosis and cellular motility but not on cell invasiveness. Accordingly, the activation of c-Myc in the context of Ras expression had only minor influence on uPAR expression but still had a profound repressive effect on uPA expression. Thus, the differential regulation of uPA and uPAR by c-Myc and Ras correlates with the effects of these two oncoproteins on cell motility, invasiveness, and survival. In conclusion, we have discovered a novel link between c-Myc and uPA/uPAR. We propose that reductions of cell motility and invasiveness could contribute to the inhibition of tumorigenesis by c-Myc and that the regulation of uPA and uPAR expression may be a component of the ability of c-Myc to reduce motility and invasiveness.

scholarly journals Protein kinase p38α signaling in dendritic cells regulates colon inflammation and tumorigenesis

2018 ◽  
Vol 115 (52) ◽  
pp. E12313-E12322 ◽  
Author(s):  
Tingting Zheng ◽  
Baohua Zhang ◽  
Ce Chen ◽  
Jingyu Ma ◽  
Deyun Meng ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lymphoid Cells ◽  
Epithelial Barrier ◽  
Epithelial Barrier Function ◽  
Colon Inflammation ◽  
Effective Immune Response ◽  
Direct Binding ◽  
Group 3 ◽  
Tr1 Cells

Dendritic cells (DCs) play pivotal roles in maintaining intestinal homeostasis, but how the DCs regulate diverse immune networks on homeostasis breakdown remains largely unknown. Here, we report that, in response to epithelial barrier disruption, colonic DCs regulate the differentiation of type 1 regulatory T (Tr1) cells through p38α-dependent IL-27 production to initiate an effective immune response. Deletion of p38α in DCs, but not in T cells, led to increased Tr1 and protected mice from dextran sodium sulfate-induced acute colitis and chronic colitis-associated colorectal cancer. We show that higher levels of IL-27 in p38α-deficient colonic cDC1s, but not cDC2s, were responsible for the increase of Tr1 cells. Moreover, p38α-dependent IL-27 enhanced IL-22 secretion from intestinal group 3 innate lymphoid cells and protected epithelial barrier function. In p38α-deficient DCs, the TAK1–MKK4/7–JNK–c-Jun axis was hyperactivated, leading to high IL-27 levels, and inhibition of the JNK–c-Jun axis suppressed IL-27 expression. ChIP assay revealed direct binding of c-Jun to the promoter of Il27p28, which was further enhanced in p38α-deficient DCs. In summary, here we identify a key role for p38α signaling in DCs in regulating intestinal inflammatory response and tumorigenesis, and our finding may provide targets for the treatment of inflammatory intestinal diseases.

scholarly journals Nodal signaling regulates endodermal cell motility and actin dynamics via Rac1 and Prex1

2012 ◽  
Vol 198 (5) ◽  
pp. 941-952 ◽  
Author(s):  
Stephanie Woo ◽  
Michael P. Housley ◽  
Orion D. Weiner ◽  
Didier Y.R. Stainier
Keyword(s):  
Cell Fate ◽  
Actin Dynamics ◽  
Migration Behavior ◽  
Nodal Signaling ◽  
Nucleotide Exchange ◽  
Random Motility ◽  
Cell Behaviors ◽  
Cell Fate Decisions ◽  
And Migration ◽  
Endodermal Cells

Embryo morphogenesis is driven by dynamic cell behaviors, including migration, that are coordinated with fate specification and differentiation, but how such coordination is achieved remains poorly understood. During zebrafish gastrulation, endodermal cells sequentially exhibit first random, nonpersistent migration followed by oriented, persistent migration and finally collective migration. Using a novel transgenic line that labels the endodermal actin cytoskeleton, we found that these stage-dependent changes in migratory behavior correlated with changes in actin dynamics. The dynamic actin and random motility exhibited during early gastrulation were dependent on both Nodal and Rac1 signaling. We further identified the Rac-specific guanine nucleotide exchange factor Prex1 as a Nodal target and showed that it mediated Nodal-dependent random motility. Reducing Rac1 activity in endodermal cells caused them to bypass the random migration phase and aberrantly contribute to mesodermal tissues. Together, our results reveal a novel role for Nodal signaling in regulating actin dynamics and migration behavior, which are crucial for endodermal morphogenesis and cell fate decisions.

scholarly journals Maturation of Monocyte-Derived DCs Leads to Increased Cellular Stiffness, Higher Membrane Fluidity, and Changed Lipid Composition

2020 ◽  
Vol 11 ◽  
Author(s):  
Jennifer J. Lühr ◽  
Nils Alex ◽  
Lukas Amon ◽  
Martin Kräter ◽  
Markéta Kubánková ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lymph Node ◽  
T Cell ◽  
T Cell Activation ◽  
Lipid Composition ◽  
Membrane Lipids ◽  
Building Blocks ◽  
Membrane Properties ◽  
Antigen Uptake ◽  
Peripheral Tissues

Dendritic cells (DCs) are professional antigen-presenting cells of the immune system. Upon sensing pathogenic material in their environment, DCs start to mature, which includes cellular processes, such as antigen uptake, processing and presentation, as well as upregulation of costimulatory molecules and cytokine secretion. During maturation, DCs detach from peripheral tissues, migrate to the nearest lymph node, and find their way into the correct position in the net of the lymph node microenvironment to meet and interact with the respective T cells. We hypothesize that the maturation of DCs is well prepared and optimized leading to processes that alter various cellular characteristics from mechanics and metabolism to membrane properties. Here, we investigated the mechanical properties of monocyte-derived dendritic cells (moDCs) using real-time deformability cytometry to measure cytoskeletal changes and found that mature moDCs were stiffer compared to immature moDCs. These cellular changes likely play an important role in the processes of cell migration and T cell activation. As lipids constitute the building blocks of the plasma membrane, which, during maturation, need to adapt to the environment for migration and DC-T cell interaction, we performed an unbiased high-throughput lipidomics screening to identify the lipidome of moDCs. These analyses revealed that the overall lipid composition was significantly changed during moDC maturation, even implying an increase of storage lipids and differences of the relative abundance of membrane lipids upon maturation. Further, metadata analyses demonstrated that lipid changes were associated with the serum low-density lipoprotein (LDL) and cholesterol levels in the blood of the donors. Finally, using lipid packing imaging we found that the membrane of mature moDCs revealed a higher fluidity compared to immature moDCs. This comprehensive and quantitative characterization of maturation associated changes in moDCs sets the stage for improving their use in clinical application.

scholarly journals Dendritic Cells and CCR7 Expression; an Important Factor for Autoimmune Diseases, Chronic Inflammation, and Cancer

2021 ◽  
Vol 22 (15) ◽  
pp. 8340
Author(s):  
Emma Probst Brandum ◽  
Astrid Sissel Jørgensen ◽  
Mette Marie Rosenkilde ◽  
Gertrud Malene Hjortø
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Antagonistic Effect ◽  
Lymphoid Tissues ◽  
Chronic Inflammatory Diseases ◽  
Inflammatory Conditions ◽  
Inflammatory State ◽  
And Control

Chemotactic cytokines—chemokines—control immune cell migration in the process of initiation and resolution of inflammatory conditions as part of the body’s defense system. Many chemokines also participate in pathological processes leading up to and exacerbating the inflammatory state characterizing chronic inflammatory diseases. In this review, we discuss the role of dendritic cells (DCs) and the central chemokine receptor CCR7 in the initiation and sustainment of selected chronic inflammatory diseases: multiple sclerosis (MS), rheumatoid arthritis (RA), and psoriasis. We revisit the binary role that CCR7 plays in combatting and progressing cancer, and we discuss how CCR7 and DCs can be harnessed for the treatment of cancer. To provide the necessary background, we review the differential roles of the natural ligands of CCR7, CCL19, and CCL21 and how they direct the mobilization of activated DCs to lymphoid organs and control the formation of associated lymphoid tissues (ALTs). We provide an overview of DC subsets and, briefly, elaborate on the different T-cell effector types generated upon DC–T cell priming. In the conclusion, we promote CCR7 as a possible target of future drugs with an antagonistic effect to reduce inflammation in chronic inflammatory diseases and an agonistic effect for boosting the reactivation of the immune system against cancer in cell-based and/or immune checkpoint inhibitor (ICI)-based anti-cancer therapy.

Endosomally Stored MHC Class II Does Not Contribute to Antigen Presentation by Dendritic Cells at Inflammatory Conditions

Traffic ◽  
2011 ◽  
Vol 12 (8) ◽  
pp. 1025-1036 ◽  
Author(s):  
Toine ten Broeke ◽  
Guillaume van Niel ◽  
Marca H. M. Wauben ◽  
Richard Wubbolts ◽  
Willem Stoorvogel
Keyword(s):  
Dendritic Cells ◽  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Inflammatory Conditions

scholarly journals Control of Dendritic Cell Migration, T Cell-Dependent Immunity, and Autoimmunity by Protein Tyrosine Phosphatase PTPN12 Expressed in Dendritic Cells

2013 ◽  
Vol 34 (5) ◽  
pp. 888-899 ◽  
Author(s):  
Inmoo Rhee ◽  
Ming-Chao Zhong ◽  
Boris Reizis ◽  
Cheolho Cheong ◽  
André Veillette
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Genetically Engineered ◽  
Lymphoid Tissues ◽  
Peripheral Tissues ◽  
Protein Tyrosine

Dendritic cells (DCs) capture and process antigens in peripheral tissues, migrate to lymphoid tissues, and present the antigens to T cells. PTPN12, also known as PTP-PEST, is an intracellular protein tyrosine phosphatase (PTP) involved in cell-cell and cell-substratum interactions. Herein, we examined the role of PTPN12 in DCs, using a genetically engineered mouse lacking PTPN12 in DCs. Our data indicated that PTPN12 was not necessary for DC differentiation, DC maturation, or cytokine production in response to inflammatory stimuli. However, it was needed for full induction of T cell-dependent immune responsesin vivo. This function largely correlated with the need of PTPN12 for DC migration from peripheral sites to secondary lymphoid tissues. Loss of PTPN12 in DCs resulted in hyperphosphorylation of the protein tyrosine kinase Pyk2 and its substrate, the adaptor paxillin. Pharmacological inhibition of Pyk2 or downregulation of Pyk2 expression also compromised DC migration, suggesting that Pyk2 deregulation played a pivotal role in the migration defect caused by PTPN12 deficiency. Together, these findings identified PTPN12 as a key regulator in the ability of DCs to induce antigen-induced T cell responses. This is due primarily to the role of PTPN12 in DC migration from peripheral sites to secondary lymphoid organs through regulation of Pyk2.

scholarly journals Epidermis instructs skin homing receptor expression in human T cells

Blood ◽  
2012 ◽  
Vol 120 (23) ◽  
pp. 4591-4598 ◽  
Author(s):  
Michelle L. McCully ◽  
Kristin Ladell ◽  
Svetlana Hakobyan ◽  
Robert E. Mansel ◽  
David A. Price ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Human Skin ◽  
Memory T Cells ◽  
Immune Surveillance ◽  
Receptor Expression ◽  
Epidermal Keratinocytes ◽  
Specific Factor ◽  
Peripheral Tissues ◽  
Preferential Expression

Abstract The localization of memory T cells to human skin is essential for long-term immune surveillance and the maintenance of barrier integrity. Although the mechanisms controlling memory T-cell migration to peripheral tissues are poorly understood, the current paradigm includes the localized secretion of “imprinting” signals from tissue-resident dendritic cells in the draining lymph nodes. Here we show that CCR8 expression by newly activated naive T cells is regulated by skin-specific factor(s) derived primarily from epidermal keratinocytes, thereby providing a mechanism for the preferential expression of CCR8 by skin-resident memory T cells. Importantly, no such effects were observed after coculture with primary cells from skin-unrelated epithelia, including mesothelium and small intestine. The keratinocyte-derived CCR8-inducing factor(s) were soluble, and independent of vitamins A and D. Furthermore, the induction of CCR8 under these conditions correlated with an increase in cutaneous lymphocyte-associated antigen expression. Our findings challenge current tissue homing paradigms, especially those involving CCR10, and emphasize the importance of steady-state epidermis rather than tissue-resident dendritic cells in controlling the localization of memory T cells within human skin.

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