scholarly journals A Live and Inactivated Chlamydia trachomatis Mouse Pneumonitis Strain Induces the Maturation of Dendritic Cells That Are Phenotypically and Immunologically Distinct

2005 ◽  
Vol 73 (3) ◽  
pp. 1568-1577 ◽  
Author(s):  
Jose Rey-Ladino ◽  
Kasra M. Koochesfahani ◽  
Michelle L. Zaharik ◽  
Caixia Shen ◽  
Robert C. Brunham
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Chlamydia Trachomatis ◽  
Mhc Class Ii ◽  
Protective Immunity ◽  
Ex Vivo ◽  
Natural Infection ◽  
Pulsed Dc ◽  
Low Levels ◽  
Dc Maturation

ABSTRACT The intracellular bacterial pathogen Chlamydia trachomatis is a major cause of sexually transmitted disease worldwide. While protective immunity does appear to develop following natural chlamydial infection in humans, early vaccine trials using heat-killed C. trachomatis resulted in limited and transient protection with possible enhanced disease during follow-up. Thus, immunity following natural infection with live chlamydia may differ from immune responses induced by immunization with inactivated chlamydia. To study this differing immunology, we used murine bone marrow-derived dendritic cells (DC) to examine DC maturation and immune effector function induced by live and UV-irradiated C. trachomatis elementary bodies (live EBs and UV-EB, respectively). DC exposed to live EBs acquired a mature DC morphology; expressed high levels of major histocompatibility complex (MHC) class II, CD80, CD86, CD40, and ICAM-1; produced elevated amounts of interleukin-12 and tumor necrosis factor alpha; and were efficiently recognized by Chlamydia-specific CD4+ T cells. In contrast, UV-EB-pulsed DC expressed low levels of CD40 and CD86 but displayed high levels of MHC class II, ICAM-1, and CD80; secreted low levels of proinflammatory cytokines; and exhibited reduced recognition by Chlamydia-specific CD4+ T cells. Adoptive transfer of live EB-pulsed DC was more effective than that of UV-EB-pulsed DC at protecting mice against challenge with live C. trachomatis. The expression of DC maturation markers and immune protection induced by UV-EB could be significantly enhanced by costimulation of DC ex vivo with UV-EB and oligodeoxynucleotides containing cytosine phosphate guanosine; however, the level of protection was significantly less than that achieved by using DC pulsed ex vivo with viable EBs. Thus, exposure of DC to live EBs results in a mature DC phenotype which is able to promote protective immunity, while exposure to UV-EB generates a semimature DC phenotype with less protective potential. This result may explain in part the differences in protective immunity induced by natural infection and immunization with whole inactivated organisms and is relevant to rational chlamydia vaccine design strategies.

scholarly journals Antigen-dependent and -independent Ca2+ Responses Triggered in T Cells by Dendritic Cells Compared with B Cells

1998 ◽  
Vol 188 (8) ◽  
pp. 1473-1484 ◽  
Author(s):  
Jérôme Delon ◽  
Nadège Bercovici ◽  
Graça Raposo ◽  
Roland Liblau ◽  
Alain Trautmann
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
Mhc Class Ii ◽  
Ex Vivo ◽  
Cell Formation ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Survival Signal

Dendritic cells (DCs) are much more potent antigen (Ag)-presenting cells than resting B cells for the activation of naive T cells. The mechanisms underlying this difference have been analyzed under conditions where ex vivo DCs or B cells presented known numbers of specific Ag–major histocompatibility complex (MHC) complexes to naive CD4+ T cells from T cell antigen receptor (TCR) transgenic mice. Several hundred Ag–MHC complexes presented by B cells were necessary to elicit the formation of a few T–B conjugates with small contact zones, and the resulting individual T cell Ca2+ responses were all-or-none. In contrast, Ag-specific T cell Ca2+ responses can be triggered by DCs bearing an average of 30 Ag–MHC complexes per cell. Formation of T–DC conjugates is Ag-independent, but in the presence of the Ag, the surface of the contact zone increases and so does the amplitude of the T cell Ca2+ responses. These results suggest that Ag is better recognized by T cells on DCs essentially because T–DC adhesion precedes Ag recognition, whereas T–B adhesion requires Ag recognition. Surprisingly, we also recorded small Ca2+ responses in T cells interacting with unpulsed DCs. Using DCs purified from MHC class II knockout mice, we provide evidence that this signal is mostly due to MHC–TCR interactions. Such an Ag-independent, MHC-triggered calcium response could be a survival signal that DCs but not B cells are able to deliver to naive T cells.

scholarly journals Inducing Tumor Immunity through the Selective Engagement of Activating Fcγ Receptors on Dendritic Cells

2002 ◽  
Vol 195 (12) ◽  
pp. 1653-1659 ◽  
Author(s):  
Alexis M. Kalergis ◽  
Jeffrey V. Ravetch
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Protective Immunity ◽  
Cell Activation ◽  
Tumor Antigens ◽  
Ex Vivo ◽  
Tumor Vaccines ◽  
Antigen Capture

Induction of tumor-specific immunity requires that dendritic cells (DCs) efficiently capture and present tumor antigens to result in the expansion and activation of tumor-specific cytotoxic T cells. The transition from antigen capture to T cell stimulation requires a maturation signal; in its absence tolerance, rather than immunity may develop. While immune complexes (ICs) are able to enhance antigen capture, they can be poor at inducing DC maturation, naive T cell activation and protective immunity. We now demonstrate that interfering with the inhibitory signal delivered by FcγRIIB on DCs converts ICs to potent maturation agents and results in T cell activation. Applying this approach to immunization with DCs pulsed ex-vivo with ICs, we have generated antigen-specific CD8+ T cells in vivo and achieved efficient protective immunity in a murine melanoma model. These data imply that ICs may normally function to maintain tolerance through the binding to inhibitory FcγRs on DCs, but they can be converted to potent immunogenic stimuli by selective engagement of activating FcγRs. This mechanism suggests a novel approach to the development of tumor vaccines.

scholarly journals Uptake of Leishmania major by dendritic cells is mediated by Fcγ receptors and facilitates acquisition of protective immunity

2006 ◽  
Vol 203 (1) ◽  
pp. 177-188 ◽  
Author(s):  
Florian Woelbing ◽  
Susanna Lopez Kostka ◽  
Katharina Moelle ◽  
Yasmine Belkaid ◽  
Cord Sunderkoetter ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
B Cell ◽  
Mhc Class Ii ◽  
Protective Immunity ◽  
Leishmania Major ◽  
Skin Lesions ◽  
Complement Receptor 3 ◽  
Deficient Mice

Uptake of Leishmania major by dendritic cells (DCs) results in activation and interleukin (IL)-12 release. Infected DCs efficiently stimulate CD4− and CD8− T cells and vaccinate against leishmaniasis. In contrast, complement receptor 3–dependent phagocytosis of L. major by macrophages (MΦ) leads exclusively to MHC class II–restricted antigen presentation to primed, but not naive, T cells, and no IL-12 production. Herein, we demonstrate that uptake of L. major by DCs required parasite-reactive immunoglobulin (Ig)G and involved FcγRI and FcγRIII. In vivo, DC infiltration of L. major–infected skin lesions coincided with the appearance of antibodies in sera. Skin of infected B cell–deficient mice and Fcγ−/− mice contained fewer parasite-infected DCs in vivo. Infected B cell–deficient mice as well as Fcγ−/− mice (all on the C57BL/6 background) showed similarly increased disease susceptibility as assessed by lesion volumes and parasite burdens. The B cell–deficient mice displayed impaired T cell priming and dramatically reduced IFN-γ production, and these deficits were normalized by infection with IgG-opsonized parasites. These data demonstrate that DC and MΦ use different receptors to recognize and ingest L. major with different outcomes, and indicate that B cell–derived, parasite-reactive IgG and DC FcγRI and FcγRIII are essential for optimal development of protective immunity.

scholarly journals Vaccination against Chlamydial Genital Tract Infection after Immunization with Dendritic Cells Pulsed Ex Vivo with Nonviable Chlamydiae

1998 ◽  
Vol 188 (5) ◽  
pp. 809-818 ◽  
Author(s):  
Hua Su ◽  
Ronald Messer ◽  
William Whitmire ◽  
Elizabeth Fischer ◽  
John C. Portis ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Sexually Transmitted Diseases ◽  
Genital Tract ◽  
Protective Immunity ◽  
Chlamydial Infection ◽  
Ex Vivo ◽  
Female Genital Tract ◽  
Genital Tract Infection ◽  
Sexually Transmitted ◽  
Pulsed Dc

Chlamydia trachomatis, an obligate intracellular bacterial pathogen of mucosal surfaces, is a major cause of preventable blindness and sexually transmitted diseases for which vaccines are badly needed. Despite considerable effort, antichlamydial vaccines have proven to be elusive using conventional immunization strategies. We report the use of murine bone marrow–derived dendritic cells (DC) pulsed ex vivo with killed chlamydiae as a novel approach to vaccination against chlamydial infection. Our results show that DC efficiently phagocytose chlamydiae, secrete IL-12 p40, and present chlamydial antigen(s) to infection sensitized CD4+ T cells. Mice immunized intravenously with chlamydial-pulsed DC produce protective immunity against chlamydial infection of the female genital tract equal to that obtained after infection with live organisms. Immunized mice shed ∼3 logs fewer infectious chlamydiae and are protected from genital tract inflammatory and obstructive disease. Protective immunity is correlated with a chlamydial-specific Th1-biased response that closely mimics the immune response produced after chlamydial infection. Thus, ex vivo antigen-pulsed DC represent a powerful tool for the study of protective immunity to chlamydial mucosal infection and for the identification of chlamydial protective antigens through reconstitution experiments. Moreover, these findings might impact the design of vaccine strategies against other medically important sexually transmitted diseases for which vaccines are sought but which have proven difficult to develop.

scholarly journals Thapsigargin-Stimulated LAD2 Human Mast Cell Line Is a Potent Cellular Adjuvant for the Maturation of Monocyte-Derived Dendritic Cells for Adoptive Cellular Immunotherapy

2021 ◽  
Vol 22 (8) ◽  
pp. 3978
Author(s):  
Pavla Taborska ◽  
Dmitry Stakheev ◽  
Jirina Bartunkova ◽  
Daniel Smrz
Keyword(s):  
Dendritic Cells ◽  
Mast Cell ◽  
Ex Vivo ◽  
Human Leukocyte ◽  
Poly I:C ◽  
Human Mast Cell ◽  
Cellular Immunotherapy ◽  
Adoptive Cellular Immunotherapy ◽  
Serum Free ◽  
Dc Maturation

The preparation of dendritic cells (DCs) for adoptive cellular immunotherapy (ACI) requires the maturation of ex vivo-produced immature(i) DCs. This maturation ensures that the antigen presentation triggers an immune response towards the antigen-expressing cells. Although there is a large number of maturation agents capable of inducing strong DC maturation, there is still only a very limited number of these agents approved for use in the production of DCs for ACI. In seeking novel DC maturation agents, we used differentially activated human mast cell (MC) line LAD2 as a cellular adjuvant to elicit or modulate the maturation of ex vivo-produced monocyte-derived iDCs. We found that co-culture of iDCs with differentially activated LAD2 MCs in serum-containing media significantly modulated polyinosinic:polycytidylic acid (poly I:C)-elicited DC maturation as determined through the surface expression of the maturation markers CD80, CD83, CD86, and human leukocyte antigen(HLA)-DR. Once iDCs were generated in serum-free conditions, they became refractory to the maturation with poly I:C, and the LAD2 MC modulatory potential was minimized. However, the maturation-refractory phenotype of the serum-free generated iDCs was largely overcome by co-culture with thapsigargin-stimulated LAD2 MCs. Our data suggest that differentially stimulated mast cells could be novel and highly potent cellular adjuvants for the maturation of DCs for ACI.

scholarly journals Methotrexate enhances antigen presentation and maturation of tumour antigen-loaded dendritic cells through NLRP3 inflammasome activation: a strategy for dendritic cell-based cancer vaccine

2021 ◽  
Vol 13 ◽  
pp. 175883592098705
Author(s):  
Gao-Na Shi ◽  
Min Hu ◽  
Chengjuan Chen ◽  
Junmin Fu ◽  
Shuai Shao ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Nlrp3 Inflammasome ◽  
Tumour Antigen ◽  
Inflammasome Activation ◽  
Antigen Uptake ◽  
Nlrp3 Inflammasome Activation ◽  
Dc Maturation

Background: Dendritic cells (DCs) are antigen-presenting cells that play a pivotal role in adaptive cell-mediated immunity by priming and activating T cells against specific tumour and pathogenic antigens. Methotrexate (MTX), a folate derivative, functions as an immunoregulatory agent. However, the possible effect of MTX on tumour antigen-loaded DCs has not yet been investigated. Methods: We analysed the effect of MTX on the maturation and function of DCs along with tumour cell lysates (TCLs). Using bone marrow-derived DCs, we investigated the effect of MTX combined TCL-loaded DCs on T cells priming and proliferation. We also tested the anti-tumour immune effect on DCs when treated with MTX and/or TCL in vivo. Results: MTX combined with TCL not only enhanced DC maturation and stimulated cytokine release but also promoted CD8+ T cell activation and proliferation. The latter was associated with increased tumour antigen uptake and cross-presentation to T cells. Mechanistically, DC maturation and antigen presentation were partly modulated by NLRP3 inflammasome activation. Furthermore, immunisation of mice with MTX and TCL-pulsed DCs before a tumour challenge significantly delayed tumour onset and retarded its growth. This protective effect was due to priming of IFN-γ releasing CD8+ T cells and enhanced killing of tumour cells by cytotoxic T lymphocytes isolated from these immunised mice. Conclusion: MTX can function as a potent adjuvant in DC vaccines by increasing antigen presentation and T cell priming. Our findings provide a new strategy for the application of DC-based anti-tumour immunotherapy.

scholarly journals Murine myeloproliferative disorder as a consequence of impaired collaboration between dendritic cells and CD4 T cells

Blood ◽  
2019 ◽  
Vol 133 (4) ◽  
pp. 319-330 ◽  
Author(s):  
Stéphanie Humblet-Baron ◽  
John S. Barber ◽  
Carlos P. Roca ◽  
Aurelie Lenaerts ◽  
Pandelakis A. Koni ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Adaptive Immune Response ◽  
Extramedullary Hematopoiesis ◽  
Myeloproliferative Disorder ◽  
Myeloid Differentiation ◽  
Normal Numbers ◽  
Congenital Deficiency

Abstract Dendritic cells (DCs) are a key cell type in the initiation of the adaptive immune response. Recently, an additional role for DCs in suppressing myeloproliferation was discovered. Myeloproliferative disorder (MPD) was observed in murine studies with constitutive depletion of DCs, as well as in patients with congenital deficiency in DCs caused by mutations in GATA2 or IRF8. The mechanistic link between DC deficiency and MPD was not predicted through the known biology and has remained an enigma. Prevailing models suggest numerical DC deficiency leads to MPD through compensatory myeloid differentiation. Here, we formally tested whether MPD can also arise through a loss of DC function without numerical deficiency. Using mice whose DCs are deficient in antigen presentation, we find spontaneous MPD that is characterized by splenomegaly, neutrophilia, and extramedullary hematopoiesis, despite normal numbers of DCs. Disease development was dependent on loss of the MHC class II (MHCII) antigen-presenting complex on DCs and was eliminated in mice deficient in total lymphocytes. Mice lacking MHCII and CD4 T cells did not develop disease. Thus, MPD was paradoxically contingent on the presence of CD4 T cells and on a failure of DCs to activate CD4 T cells, trapping the cells in a naive Flt3 ligand–expressing state. These results identify a novel requirement for intercellular collaboration between DCs and CD4 T cells to regulate myeloid differentiation. Our findings support a new conceptual framework of DC biology in preventing MPD in mice and humans.

scholarly journals Small amounts of superantigen, when presented on dendritic cells, are sufficient to initiate T cell responses.

1993 ◽  
Vol 178 (2) ◽  
pp. 633-642 ◽  
Author(s):  
N Bhardwaj ◽  
J W Young ◽  
A J Nisanian ◽  
J Baggers ◽  
R M Steinman
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Mhc Class Ii ◽  
Cell Receptor ◽  
Class Ii ◽  
Cell Mediated Immunity ◽  
Quiescent T Cells ◽  
Antigen Presenting

Dendritic cells are potent antigen-presenting cells for several primary immune responses and therefore provide an opportunity for evaluating the amounts of cell-associated antigens that are required for inducing T cell-mediated immunity. Because dendritic cells express very high levels of major histocompatibility complex (MHC) class II products, it has been assumed that high levels of ligands bound to MHC products ("signal one") are needed to stimulate quiescent T cells. Here we describe quantitative aspects underlying the stimulation of human blood T cells by a bacterial superantigen, staphylococcal enterotoxin A (SEA). The advantages of superantigens for quantitative studies of signal one are that these ligands: (a) engage MHC class II and the T cell receptor but do not require processing; (b) are efficiently presented to large numbers of quiescent T cells; and (c) can be pulsed onto dendritic cells before their application to T cells. Thus one can relate amounts of dendritic cell-associated SEA to subsequent lymphocyte stimulation. Using radioiodinated SEA, we noted that dendritic cells can bind 30-200 times more superantigen than B cells and monocytes. Nevertheless, this high SEA binding does not underlie the strong potency of dendritic cells to present antigen to T cells. Dendritic cells can sensitize quiescent T cells, isolated using monoclonals to appropriate CD45R epitopes, after a pulse of SEA that occupies a maximum of 0.1% of surface MHC class II molecules. This corresponds to an average of 2,000 molecules per dendritic cell. At these low doses of bound SEA, monoclonal antibodies to CD3, CD4, and CD28 almost completely block T cell proliferation. In addition to suggesting new roles for MHC class II on dendritic cells, especially the capture and retention of ligands at low external concentrations, the data reveal that primary T cells can generate a response to exceptionally low levels of signal one as long as these are delivered on dendritic cells.

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