scholarly journals Expression of the Phosphatase Ppef2 Controls Survival and Function of CD8+ Dendritic Cells

2018 ◽  
Author(s):  
Markus Zwick ◽  
Thomas Ulas ◽  
Yi-Li Cho ◽  
Christine Ried ◽  
Leonie Grosse ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Protein Phosphatase ◽  
Apoptotic Cell ◽  
Model Systems ◽  
Toll Like Receptor ◽  
Cell Responses ◽  
Ef Hands ◽  
And Function ◽  
Dc Maturation

AbstractApoptotic cell death of Dendritic cells (DCs) is critical for immune homeostasis. Although intrinsic mechanisms controlling DC death have not been fully characterized up to now, experimentally enforced inhibition of DC-death causes various autoimmune diseases in model systems. We have generated mice deficient for Protein Phosphatase with EF-Hands 2 (Ppef2), which is selectively expressed in CD8+ DCs, but not in other related DC subtypes such as tissue CD103+ DCs. Ppef2 is down-regulated rapidly upon maturation of DCs by toll-like receptor stimuli, but not upon triggering of CD40. Ppef2-deficient CD8+ DCs accumulate the pro-apoptotic Bcl-2-like protein 11 (Bim) and show increased apoptosis and reduced competitve repopulation capacities. Furthermore, Ppef2−/−CD8+ DCs have strongly diminished antigen presentation capacities in vivo, as CD8+ T cells primed by Ppef2−/− CD8+ DCs undergo reduced expansion. In conclusion, our data suggests that Ppef2 is crucial to support survival of immature CD8+ DCs, while Ppef2 down-regulation during DC-maturation limits T cell responses.

scholarly journals Dendritic Cell Responses to Early Murine Cytomegalovirus Infection

2003 ◽  
Vol 197 (7) ◽  
pp. 885-898 ◽  
Author(s):  
Marc Dalod ◽  
Tanya Hamilton ◽  
Rachelle Salomon ◽  
Thais P. Salazar-Mather ◽  
Stanley C. Henry ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphocyte Activation ◽  
Murine Cytomegalovirus ◽  
Cell Responses ◽  
Dc Maturation

Differentiation of dendritic cells (DCs) into particular subsets may act to shape innate and adaptive immune responses, but little is known about how this occurs during infections. Plasmacytoid dendritic cells (PDCs) are major producers of interferon (IFN)-α/β in response to many viruses. Here, the functions of these and other splenic DC subsets are further analyzed after in vivo infection with murine cytomegalovirus (MCMV). Viral challenge induced PDC maturation, their production of high levels of innate cytokines, and their ability to activate natural killer (NK) cells. The conditions also licensed PDCs to efficiently activate CD8 T cells in vitro. Non-plasmacytoid DCs induced T lymphocyte activation in vitro. As MCMV preferentially infected CD8α+ DCs, however, restricted access to antigens may limit plasmacytoid and CD11b+ DC contribution to CD8 T cell activation. IFN-α/β regulated multiple DC responses, limiting viral replication in all DC and IL-12 production especially in the CD11b+ subset but promoting PDC accumulation and CD8α+ DC maturation. Thus, during defense against a viral infection, PDCs appear specialized for initiation of innate, and as a result of their production of IFN-α/β, regulate other DCs for induction of adaptive immunity. Therefore, they may orchestrate the DC subsets to shape endogenous immune responses to viruses.

scholarly journals CD103+ pulmonary dendritic cells preferentially acquire and present apoptotic cell–associated antigen

2011 ◽  
Vol 208 (9) ◽  
pp. 1789-1797 ◽  
Author(s):  
A. Nicole Desch ◽  
Gwendalyn J. Randolph ◽  
Kenneth Murphy ◽  
Emmanuel L. Gautier ◽  
Ross M. Kedl ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Apoptotic Cell ◽  
T Cell Responses ◽  
Cytotoxic T Cell ◽  
Soluble Antigen ◽  
Cell Responses ◽  
Inflammatory Conditions ◽  
Cytotoxic T Cell Responses

Cells undergoing programmed cell death (apoptosis) are removed in situ by macrophages and dendritic cells (DCs) through a specialized form of phagocytosis (efferocytosis). In the lung, there are two primary DC subsets with the potential to migrate to the local lymph nodes (LNs) and initiate adaptive immune responses. In this study, we show that only CD103+ DCs were able to acquire and transport apoptotic cells to the draining LNs and cross present apoptotic cell–associated antigen to CD8 T cells. In contrast, both the CD11bhi and the CD103+ DCs were able to ingest and traffic latex beads or soluble antigen. CD103+ DCs selectively exhibited high expression of TLR3, and ligation of this receptor led to enhanced in vivo cytotoxic T cell responses to apoptotic cell–associated antigen. The selective role for CD103+ DCs was confirmed in Batf3−/− mice, which lack this DC subtype. Our findings suggest that CD103+ DCs are the DC subset in the lung that captures and presents apoptotic cell–associated antigen under homeostatic and inflammatory conditions and raise the possibility for more focused immunological targeting to CD8 T cell responses.

scholarly journals Cell-intrinsic role for IFN-α–STAT1 signals in regulating murine Peyer patch plasmacytoid dendritic cells and conditioning an inflammatory response

Blood ◽  
2011 ◽  
Vol 118 (14) ◽  
pp. 3879-3889 ◽  
Author(s):  
Haiyan S. Li ◽  
Alexander Gelbard ◽  
Gustavo J. Martinez ◽  
Eiji Esashi ◽  
Huiyuan Zhang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Type I ◽  
Toll Like Receptor ◽  
Ccr9 Expression ◽  
A Cell ◽  
And Function ◽  
Antigen Presenting

Abstract Plasmacytoid dendritic cells (pDCs) reside in bone marrrow and lymphoid organs in homeostatic conditions and typically secrete abundant quantities of type I interferons (IFNs) on Toll-like receptor triggering. Recently, a pDC population was identified within Peyer patches (PPs) of the gut that is distinguished by its lack of IFN production; however, the relationship of PP pDCs to pDCs in other organs has been unclear. We report that PP pDCs are derived from common DC progenitors and accumulate in response to Fms-like tyrosine kinase 3 ligand, yet appear divergent in transcription factor profile and surface marker phenotype, including reduced E2-2 and CCR9 expression. Type I IFN signaling via STAT1 has a cell-autonomous role in accrual of PP pDCs in vivo. Moreover, IFN-α enhances pDC generation from DC progenitors by a STAT1-dependent mechanism. pDCs that have been developed in the presence of IFN-α resemble PP pDCs, produce inflammatory cytokines, stimulate Th17 cell generation, and fail to secrete IFN-α on Toll-like receptor engagement. These results indicate that IFN-α influences the development and function of pDCs by inducing emergence of an inflammatory (Th17-inducing) antigen-presenting subset, and simultaneously regulating accumulation of pDCs in the intestinal microenvironment.

Selective Rac1 inhibition in dendritic cells diminishes apoptotic cell uptake and cross-presentation in vivo

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 742-749 ◽  
Author(s):  
Kristen M. Kerksiek ◽  
Florence Niedergang ◽  
Philippe Chavrier ◽  
Dirk H. Busch ◽  
Thomas Brocker
Keyword(s):  
Transgene Expression ◽  
Apoptotic Cell ◽  
Cell Uptake ◽  
Special Role ◽  
Cross Presentation ◽  
Cell Responses ◽  
Cytoskeletal Regulation ◽  
Guanosine Triphosphatase ◽  
And Function

Abstract To better understand the influence of cytoskeletal regulation on dendritic cell (DC) function in vivo, the Rho guanosine triphosphatase (GTPase) Rac1 was selectively inhibited in DCs in transgenic (Tg) mice. Although transgene expression did not interfere with the migratory capacities of DC in vivo, a decreased uptake of fluorescent probes was observed. Interestingly, the absence of full Rac1 function most strongly affected the development and function of CD8+ DCs. Apoptotic cell uptake was severely reduced in Tg mice, impairing subsequent DC-mediated cross-presentation and priming of bacteria-specific T-cell responses. These findings highlight a special role for Rac1 in the capacity of CD8+ DCs to endocytose apoptotic cells and prime T cells via cross-presentation.

scholarly journals CD8− DCs induce IL-12–independent Th1 differentiation through Delta 4 Notch-like ligand in response to bacterial LPS

2007 ◽  
Vol 204 (7) ◽  
pp. 1525-1531 ◽  
Author(s):  
Dimitris Skokos ◽  
Michel C. Nussenzweig
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Toll Like Receptor ◽  
T Helper ◽  
Cell Responses ◽  
Ligand Expression ◽  
Th 1 ◽  
Dependent Mechanism

Toll-like receptor (TLR) ligation is believed to skew T cell responses toward T helper (Th)1 differentiation by inducing interleukin (IL)-12 secretion by CD8+ dendritic cells (DCs). However, TLR-dependent Th1 responses occur in the absence of IL-12. To determine how DCs induce Th1 differentiation in the absence of IL-12, we examined the response of IL-12–deficient DCs to bacterial lipopolysaccharide (LPS). We find that LPS activates MyD88-dependent Delta 4 Notch-like ligand expression by CD8− DCs, and that these cells direct Th1 differentiation by an IL-12–independent and Notch-dependent mechanism in vitro and in vivo. Thus, activation of the two DC subsets by TLR4 leads to Th1 responses by two distinct MyD88-dependent pathways.

Cytotoxic T Cell Responses against Mesothelioma by Apoptotic Cell-pulsed Dendritic Cells

2004 ◽  
Vol 169 (12) ◽  
pp. 1322-1330 ◽  
Author(s):  
Frédéric Ebstein ◽  
Carole Sapede ◽  
Pierre-Joseph Royer ◽  
Marie Marcq ◽  
Catherine Ligeza-Poisson ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Apoptotic Cell ◽  
T Cell Responses ◽  
Cytotoxic T Cell ◽  
Cell Responses ◽  
Cytotoxic T Cell Responses

Tumor spheroids and organoids as preclinical model systems

2021 ◽  
Vol 33 (3) ◽  
pp. 229-234
Author(s):  
Aria Baniahmad
Keyword(s):  
Apoptotic Cell ◽  
Model Systems ◽  
Adherent Cell ◽  
Preclinical Model ◽  
Cancer Tissue ◽  
Tumor Spheroids ◽  
Cancer Models ◽  
Cancer Multiple ◽  
Cell Cell

Abstract The generation of three-dimensional (3D) cancer models is a novel and fascinating development in the study of personalized medicine and tumor-specific drug delivery. In addition to the classical two-dimensional (2D) adherent cell culture models, 3D spheroid and organoid cancer models that mimic the microenvironment of cancer tissue are emerging as an important preclinical model system. 3D cancer models form, similar to cancer, multiple cell–cell and cell–extracellular matrix interactions and activate different cellular cascades/pathways, like proliferation, quiescence, senescence, and necrotic or apoptotic cell death. Further, it is possible to analyze genetic variations and mutations, the microenvironment of cell–cell interactions, and the uptake of therapeutics and nanoparticles in nanomedicine. Important is also the analysis of cancer stem cells (CSCs), which could play key roles in resistance to therapy and cancer recurrence. Tumor spheroids can be generated from one tumor-derived cell line or from co-culture of two or more cell lines. Tumor organoids can be derived from tumors or may be generated from CSCs that differentiate into multiple facets of cancerous tissue. Similarly, tumorspheres can be generated from a single CSC. By transplanting spheroids and organoids into immune-deficient mice, patient-derived xenografts can serve as a preclinical model to test therapeutics in vivo. Although the handling and analysis of 3D tumor spheroids and organoids is more complex, it will provide insights into various cancer processes that cannot be provided by 2D culture. Here a short overview of 3D tumor systems as preclinical models is provided.

scholarly journals 846 Pre-clinical validation of a FLT3L-fusion protein for dendritic cell expansion and anti-tumor efficacy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A887-A887
Author(s):  
Michelle Kuhne ◽  
Hamlet Chu ◽  
Sarah Ng ◽  
Christopher Clarke ◽  
Brian Carr ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Fusion Protein ◽  
Tyrosine Kinase ◽  
Single Agent ◽  
Tumor Growth Inhibition ◽  
Cell Responses ◽  
Dose Dependent ◽  
Cell Death Protein

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 efficacy.MethodsGS-3583 is a fusion protein composed of the extracellular domain (ECD) 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. To evaluate the therapeutic efficacy of FLT3 stimulation in vivo, a mouse surrogate mGS-3583was designed using the ECD of mouse FLT3L fused to an engineered mouse IgG2a Fc withattenuated binding to mouse FcgRs.Results mGS-3583 bound to recombinant mouse FLT3 with an estimated affinity of 15 nM, and to mouse FLT3-expressing cells with an EC50 of 0.15 nM. In vivo, mGS-3583 showed single agent dose-dependent tumor growth inhibition (TGI) in tumors that correlated with peripheral and intratumoral cDC1 expansion. In tumors with no initial immune infiltration, mGS-3583 led to an influx of T cells into the tumors. In addition to single agent efficacy, mGS-3583 combined effectively with programmed cell death protein (ligand)-1 (PD(L)-1) pathway blockade.ConclusionsIn vivo expansion of dendritic cells can convert uninflamed (cold) tumors to immunologically active (hot) tumors and initiate productive anti-tumor immune responses. These findings support the development GS-3583 as a promising candidate for cancer immunotherapy.

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