The Lymphoid Chemokine CCL21 Enhances the Migration- and CTL-Inducing Functions of Dendritic Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1127-1127
Author(s):  
Cheol Yi Hong ◽  
Pawel Kalinski ◽  
Hyeoung-Joon Kim ◽  
Je-Jung Lee
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd8 T Cells ◽  
Conflicts Of Interest ◽  
Cytotoxic T Cells ◽  
Lymphoid Organ ◽  
Lymphoid Organs ◽  
Dependent Manner ◽  
Migratory Capacity ◽  
Secondary Lymphoid Organs

Abstract Abstract 1127 The migration of dendritic cells (DCs) to secondary lymphoid organs is very important to elicit an adaptive immune response in cancer immunotherapy. Here, we show the effect of lymphoid cytokine on the ability of maturing DCs to migrate in response to the lymph node-associated chemokines. The secondary-lymphoid organ chemokine (SLC/CCL21) during DC maturation dramatically enhanced DC migratory capacity responding to CCL21 and CCL19, and, moreover, produced strongly enhanced cytotoxic T cells, although it did not affect the expression of cell surface markers such as CD80, CD83, CD86, and CCR7 and the production of cytokines such as IL-12p70, IL-10, and IL-23. Mature DCs (mDCs) exposed by chemokine produced higher levels of CXCL10 (IP-10) that is one of the chemokines involved in Th1 attraction, but did not affect the production of Th2-attracting cytokine CCL22, compared with unstimulated mDCs. CCL21-exposed DCs induced strongly enhanced numbers of the interferon-g (IFN-g)-expressing antigen-specific CD8+ T cells against tumor-specific antigens in an CXCL10-dependent manner. Cytotoxic CD8+ T cells stimulated with CCL21-exposed DCs expressed higher level of IFN-g than those stimulated with control mDCs. Interestingly, generation of cytotoxic T cells (CTLs) stimulated by TNFa/IL-1b/IL-6/PGE2-treated DCs (sDCs) supplemented with IP-10 produced strong cytotoxic T cells expressing higher level of IFN-g. Tetramer assay showed that CCL21-treated DCs enhanced generation of antigen-specific CTLs. Taken together, our data suggest that mDCs pre-stimulated by chemokine CCL21 enhanced migratory capacity to secondary lymphoid organs and produced strong cytotoxic T cells via IP-10 signaling pathway. Disclosures: No relevant conflicts of interest to declare.

scholarly journals IL-10 Directly Activates and Expands Tumor-Resident CD8+ T Cells without De Novo Infiltration from Secondary Lymphoid Organs

2012 ◽  
Vol 72 (14) ◽  
pp. 3570-3581 ◽  
Author(s):  
Jan Emmerich ◽  
John B. Mumm ◽  
Ivan H. Chan ◽  
Drake LaFace ◽  
Hoa Truong ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
De Novo ◽  
Lymphoid Organs ◽  
Secondary Lymphoid Organs

scholarly journals Human Dendritic Cells: Ontogeny and Their Subsets in Health and Disease

2018 ◽  
Vol 6 (4) ◽  
pp. 88 ◽  
Author(s):  
Sandra Solano-Gálvez ◽  
Sonia Tovar-Torres ◽  
María Tron-Gómez ◽  
Ariane Weiser-Smeke ◽  
Diego Álvarez-Hernández ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Current Knowledge ◽  
Lymphoid Organ ◽  
Heterogeneous Population ◽  
Health And Disease ◽  
Human Dendritic Cells ◽  
Activation Status

Dendritic cells (DCs) are a type of cells derived from bone marrow that represent 1% or less of the total hematopoietic cells of any lymphoid organ or of the total cell count of the blood or epithelia. Dendritic cells comprise a heterogeneous population of cells localized in different tissues where they act as sentinels continuously capturing antigens to present them to T cells. Dendritic cells are uniquely capable of attracting and activating naïve CD4+ and CD8+ T cells to initiate and modulate primary immune responses. They have the ability to coordinate tolerance or immunity depending on their activation status, which is why they are also considered as the orchestrating cells of the immune response. The purpose of this review is to provide a general overview of the current knowledge on ontogeny and subsets of human dendritic cells as well as their function and different biological roles.

Regulation of Tim-3 function by binding to phosphatidylserine

2021 ◽  
Vol 478 (22) ◽  
pp. 3999-4004
Author(s):  
Lawrence P. Kane
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Transmembrane Protein ◽  
Cytotoxic T Cells ◽  
Cross Presentation ◽  
First Time

Tim-3 is a transmembrane protein that is highly expressed on subsets of chronically stimulated CD4+ helper and CD8+ cytotoxic T cells, with more transient expression during acute activation and infection. Tim-3 is also constitutively expressed by multiple types of myeloid cells. Like other TIM family members, Tim-3 can bind to phosphatidylserine displayed by apoptotic cells, and this interaction has been shown to mediate uptake of such cells by dendritic cells and cross-presentation of antigens to CD8+ T cells. In contrast, how the recognition of PS by Tim-3 might regulate the function of Tim-3+ T cells is not known. In their recent paper, Lemmon and colleagues demonstrate for the first time that recognition of PS by Tim-3 leads to enhanced T cell activation.

scholarly journals Dendritic cells require NIK for CD40-dependent cross-priming of CD8+ T cells

2015 ◽  
Vol 112 (47) ◽  
pp. 14664-14669 ◽  
Author(s):  
Anand K. Katakam ◽  
Hans Brightbill ◽  
Christian Franci ◽  
Chung Kung ◽  
Victor Nunez ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd8 T Cells ◽  
Lymphoid Organs ◽  
Serine Threonine Kinase ◽  
Cross Presentation ◽  
Inflammatory Stimuli ◽  
Dc Maturation

Dendritic cells (DCs) link innate and adaptive immunity and use a host of innate immune and inflammatory receptors to respond to pathogens and inflammatory stimuli. Although DC maturation via canonical NF-κB signaling is critical for many of these functions, the role of noncanonical NF-κB signaling via the serine/threonine kinase NIK (NF-κB–inducing kinase) remains unclear. Because NIK-deficient mice lack secondary lymphoid organs, we generated transgenic mice with targeted NIK deletion in CD11c+ cells. Although these mice exhibited normal lymphoid organs, they were defective in cross-priming naive CD8+ T cells following vaccination, even in the presence of anti-CD40 or polyinosinic:polycytidylic acid to induce DC maturation. This impairment reflected two intrinsic defects observed in splenic CD8+ DCs in vitro, namely antigen cross-presentation to CD8+ T cells and secretion of IL-12p40, a cytokine known to promote cross-priming in vivo. In contrast, antigen presentation to CD4+ T cells was not affected. These findings reveal that NIK, and thus probably the noncanonical NF-κB pathway, is critical to allow DCs to acquire the capacity to cross-present antigen and prime CD8 T cells after exposure to licensing stimuli, such as an agonistic anti-CD40 antibody or Toll-like receptor 3 ligand.

scholarly journals Expansion of HIV-specific CD4+ and CD8+ T cells by dendritic cells transfected with mRNA encoding cytoplasm- or lysosome-targeted Nef

Blood ◽  
2006 ◽  
Vol 107 (5) ◽  
pp. 1963-1969 ◽  
Author(s):  
Daniel G. Kavanagh ◽  
Daniel E. Kaufmann ◽  
Sherzana Sunderji ◽  
Nicole Frahm ◽  
Sylvie Le Gall ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Cytotoxic T Cells ◽  
T Cell Response ◽  
Peripheral Blood Mononuclear ◽  
T Cell Lines

Transfection with synthetic mRNA is a safe and efficient method of delivering antigens to dendritic cells for immunotherapy. Targeting antigens to the lysosome can sometimes enhance the CD4+ T-cell response. We transfected antigen-presenting cells (APCs) with mRNA encoding Gag-p24 and cytoplasmic, lysosomal, and secreted forms of Nef. Antigen-specific cytotoxic T cells were able to lyse the majority of transfected targets, indicating that transfection was efficient. Transfection of APCs with a Nef construct bearing lysosomal targeting signals produced rapid and prolonged antigen presentation to CD4+ and CD8+ T cells. Polyclonal CD4+ and CD8+ T-cell lines recognizing multiple distinct epitopes were expanded by coculture of transfected dendritic cells with peripheral blood mononuclear cells from viremic and aviremic HIV-infected subjects. Importantly, lysosome-targeted antigen drove a significantly greater expansion of Nef-specific CD4+ T cells than cytoplasmic antigen. The frequency of recognition of CD8 but not CD4 epitopes by mRNA-expanded T cells was inversely proportional to sequence entropy and was similar to ex vivo responses from a large chronic cohort. Thus human dendritic cells transfected with mRNA encoding lysosome-targeted HIV antigen can expand a broad, polyclonal repertoire of antiviral T cells, offering a promising approach to HIV immunotherapy.

scholarly journals Similar antigen cross-presentation capacity and phagocytic functions in all freshly isolated human lymphoid organ–resident dendritic cells

2013 ◽  
Vol 210 (5) ◽  
pp. 1035-1047 ◽  
Author(s):  
Elodie Segura ◽  
Mélanie Durand ◽  
Sebastian Amigorena
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Lymphoid Organ ◽  
Lymphoid Organs ◽  
Endocytic Pathway ◽  
Soluble Antigen ◽  
Cross Presentation ◽  
Antigen Presenting ◽  
Secondary Lymphoid Organs

Dendritic cells (DCs) represent a heterogeneous population of antigen-presenting cells that initiate and orient immune responses in secondary lymphoid organs. In mice, lymphoid organ–resident CD8+ DCs are specialized at cross-presentation and have developed specific adaptations of their endocytic pathway (high pH, low degradation, and high export to the cytosol). In humans, blood BDCA3+ DCs were recently shown to be the homologues of mouse CD8+ DCs. They were also proposed to cross-present antigens more efficiently than other blood DC subsets after in vitro activation, suggesting that in humans cross-presentation is restricted to certain DC subsets. The DCs that cross-present antigen physiologically, however, are the ones present in lymphoid organs. Here, we show that freshly isolated tonsil-resident BDCA1+ DCs, BDCA3+ DCs, and pDCs all cross-present soluble antigen efficiently, as compared to macrophages, in the absence of activation. In addition, BDCA1+ and BDCA3+ DCs display similar phagosomal pH and similar production of reactive oxygen species in their phagosomes. All three DC subsets, in contrast to macrophages, also efficiently export internalized proteins to the cytosol. We conclude that all freshly isolated lymphoid organ–resident human DCs, but not macrophages, display high intrinsic cross-presentation capacity.

scholarly journals Mice Lacking Expression of the Chemokines Ccl21-Ser and Ccl19 (plt Mice) Demonstrate Delayed but Enhanced T Cell Immune Responses

2001 ◽  
Vol 193 (2) ◽  
pp. 207-218 ◽  
Author(s):  
Shigeyuki Mori ◽  
Hideki Nakano ◽  
Kentaro Aritomi ◽  
Chrong-Reen Wang ◽  
Michael D. Gunn ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cell Response ◽  
T Cell Response ◽  
Lymphoid Organs ◽  
Cell Responses ◽  
T Cell Immune Responses ◽  
Secondary Lymphoid Organs

The paucity of lymph node T cells (plt) mutation leads to a loss of CCL21 and CCL19 expression in secondary lymphoid organs. plt mice have defects in the migration of naive T cells and activated dendritic cells into the T cell zones of lymphoid organs, suggesting that they would have defects in T cell immune responses. We now demonstrate T cell responses in plt mice are delayed but ultimately enhanced. Responses to contact sensitization are decreased at day 2 after priming but increased at day 6. After subcutaneous immunization, antigen-specific T cell proliferation and cytokine production in plt mice are increased and remain markedly elevated for at least 8 wk. Compared with wild-type mice, a proportion of T cell response in plt mice are shifted to the spleen, and prior splenectomy reduces the T cell response in draining lymph nodes. After immunization of plt mice, T cells and dendritic cells colocalize in the superficial cortex of lymph nodes and in splenic bridging channels, but not in T cell zones. These results demonstrate that plt mice mount robust T cell responses despite the failure of naive T cells and activated dendritic cells to enter the thymus dependent areas of secondary lymphoid organs.

scholarly journals Human Dendritic Cells Skew Isotype Switching of CD40-activated Naive B Cells towards IgA1 and IgA2

1997 ◽  
Vol 185 (11) ◽  
pp. 1909-1918 ◽  
Author(s):  
Jérôme Fayette ◽  
Bertrand Dubois ◽  
Stéphane Vandenabeele ◽  
Jean-Michel Bridon ◽  
Béatrice Vanbervliet ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Culture Conditions ◽  
Lymphoid Organs ◽  
Cell Growth And Differentiation ◽  
Secondary Lymphoid Organs

Within T cell–rich areas of secondary lymphoid organs, interdigitating dendritic cells recruit antigen-specific T cells that then induce B cells to secrete Igs. This study investigates the possible role(s) of dendritic cells in the regulation of human B cell responses. In the absence of exogenous cytokines, in vitro generated dendritic cells (referred to as Dendritic Langerhans cells, D-Lc) induced surface IgA expression on ∼10% of CD40-activated naive sIgD+ B cells. In the presence of IL-10 and TGF-β, a combination of cytokines previously identified for its capacity to induce IgA switch, D-Lc strongly potentiated the induction of sIgA on CD40-activated naive B cells from 5% to 40–50%. D-Lc alone did not induce the secretion of IgA by CD40-activated naive B cells, which required further addition of IL-10. Furthermore, D-Lc skewed towards the IgA isotype at the expense of IgG, the Ig production of CD40-activated naive B cells cultured in the presence of IL-10 and TGF-β. Importantly, under these culture conditions, both IgA1 and IgA2 were detected. In the presence of IL-10, secretion of IgA2 by CD40-activated naive B cells could be detected only in response to D-Lc and was further enhanced by TGF-β. Collectively, these results suggest that in addition to activating T cells in the extrafollicular areas of secondary lymphoid organs, human D-Lc also directly modulate T cell–dependent B cell growth and differentiation, by inducing the IgA isotype switch.

CD4+ and CD8+ anergic T cells induced by interleukin-10–treated human dendritic cells display antigen-specific suppressor activity

Blood ◽  
2002 ◽  
Vol 99 (7) ◽  
pp. 2468-2476 ◽  
Author(s):  
Kerstin Steinbrink ◽  
Edith Graulich ◽  
Sebastian Kubsch ◽  
Jürgen Knop ◽  
Alexander H. Enk
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Interleukin 10 ◽  
Cell Contact ◽  
Dependent Manner ◽  
Suppressor Activity ◽  
T Cell Clone ◽  
Anergic T Cells

Interleukin-10 (IL-10)–treated dendritic cells (DCs) induce an alloantigen- or peptide-specific anergy in various CD4+ and CD8+ T-cell populations. In the present study, we analyzed whether these anergic T cells are able to regulate antigen-specific immunity. Coculture experiments revealed that alloantigen-specific anergic CD4+ and CD8+ T cells suppressed proliferation of syngeneic T cells in a dose-dependent manner. The same effect was observed when the hemagglutinin-specific CD4+T-cell clone HA1.7 or tyrosinase-specific CD8+ T cells were cocultured with anergic T cells of the same specificity. Anergic T cells did not induce an antigen-independent bystander inhibition. Suppression was dependent on cell-to-cell contact between anergic and responder T cells, required activation by antigen-loaded DCs, and was not mediated by supernatants of anergic T cells. Furthermore, anergic T cells displayed an increased extracellular and intracellular expression of cytotoxic T-lymphocye antigen (CTLA)–4 molecules, and blocking of the CTLA-4 pathway restored the T-cell proliferation up to 70%, indicating an important role of the CTLA-4 molecule in the suppressor activity of anergic T cells. Taken together, our experiments demonstrate that anergic T cells induced by IL-10–treated DCs are able to suppress activation and function of T cells in an antigen-specific manner. Induction of anergic T cells might be exploited therapeutically for suppression of cellular immune responses in allergic or autoimmune diseases with identified (auto) antigens.

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