scholarly journals Tumor-reactive T cells are licensed by dendritic cells located in spatially different tissues: implications for dendritic cell vaccines

Oncotarget ◽  
2021 ◽  
Vol 12 (16) ◽  
pp. 1631-1633
Author(s):  
Nadine Santana-Magal ◽  
Leen Farhat-Younis ◽  
Yaron Carmi
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Dendritic Cell Vaccines ◽  
Different Tissues

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.

scholarly journals Restricted Clonal Expression of IL-2 By Naive T Cells Reflects Differential Dynamic Interactions with Dendritic Cells

2003 ◽  
Vol 198 (1) ◽  
pp. 123-132 ◽  
Author(s):  
Vincent Hurez ◽  
Arman Saparov ◽  
Albert Tousson ◽  
Michael J. Fuller ◽  
Takekazu Kubo ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Gene Transcription ◽  
Cell Populations ◽  
Intrinsic Variability ◽  
Dynamic Interactions ◽  
Transgenic Model ◽  
Transient Interactions

Limited frequencies of T cells express IL-2 in primary antigenic responses, despite activation marker expression and proliferation by most clonal members. To define the basis for restricted IL-2 expression, a videomicroscopic system and IL-2 reporter transgenic model were used to characterize dendritic cell (DC)–T cell interactions. T cells destined to produce IL-2 required prolonged interactions with DCs, whereas most T cells established only transient interactions with DCs and were activated, but did not express IL-2. Extended conjugation of T cells with DCs was not always sufficient to initiate IL-2 expression. Thus, there is intrinsic variability in clonal T cell populations that restricts IL-2 commitment, and prolonged engagement with mature DCs is necessary, but not sufficient, for IL-2 gene transcription.

TREM-1 modulates dendritic cell maturation and dendritic cell–mediated T cell activation induced by ox-LDL

2020 ◽  
Author(s):  
Yunkai Wang ◽  
Jie Wang ◽  
Lu Han ◽  
Yun Li Shen ◽  
Jie Yun You ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Peripheral Blood ◽  
Dendritic Cell Maturation ◽  
Cell Maturation ◽  
Blood Monocytes

Abstract Background: Triggering receptor expressed on myeloid cells (TREM)-1is identified as a major upstream proatherogenic receptor. However, the cellular processes modulated by TREM-1 in the development of atherosclerosis and plaque destabilization has not been fully elucidated. In this study, we investigated the effects of TREM-1 on dendritic cell maturation and dendritic cell–mediated T-cell activation induced by oxidized low-density lipoprotein (ox-LDL) in atherogenesis. Methods: Human peripheral blood monocytes were differentiated to dendritic cells and stimulated by ox-LDL. Naive autologous T cells were co-cultured with pretreated dendritic cells.The expressionof TREM-1 and the production of inflammatory cytokines were assessed by real-time PCR, western blot and ELISA.The expression of immune factors was determined with FACS to evaluate dendritic cell maturation and T-cell activation. Results: Stimulation with ox-LDL promoted dendritic cell maturation, TREM-1 expression and T-cell activation, and exposure of T cells to ox-LDL-treated dendritic cells induced production of interferon-γ and IL-17. Blocking TREM-1 suppressed dendritic cell maturation with low expression of CD1a, CD40, CD86 and HLA-DR, decreased production of TNF-α, IL-1β, IL-6 and MCP-1, and increased secretion of TGF-β and IL-10. In addition, stimulation of ox-LDL induced miR-155, miR-27, Let-7c and miR-185 expression, whereas inhibition of TREM-1 repressed miRNA-155. Silencing TREM-1 or miRNA-155 increased SOCS1 expression induced by ox-LDL. T cells derived from carotid atherosclerotic plaques or healthy individuals showed similar result patterns. Conclusion: These data suggest that TREM-1 modulates maturation of dendritic cells and activation of plaque T cells induced by ox-LDL, a pivotal player in atherogenesis.

scholarly journals The Role of Dendritic Cells in TB and HIV Infection

2020 ◽  
Vol 9 (8) ◽  
pp. 2661
Author(s):  
Rachel Abrahem ◽  
Emerald Chiang ◽  
Joseph Haquang ◽  
Amy Nham ◽  
Yu-Sam Ting ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Hiv Infection ◽  
Cell Response ◽  
Defense Mechanism ◽  
Critical Role ◽  
Cytokine Release ◽  
T Helper 1

Dendritic cells are the principal antigen-presenting cells (APCs) in the host defense mechanism. An altered dendritic cell response increases the risk of susceptibility of infections, such as Mycobacterium tuberculosis (M. tb), and the survival of the human immunodeficiency virus (HIV). The altered response of dendritic cells leads to decreased activity of T-helper-1 (Th1), Th2, Regulatory T cells (Tregs), and Th17 cells in tuberculosis (TB) infections due to a diminishment of cytokine release from these APCs, while HIV infection leads to DC maturation, allowing DCs to migrate to lymph nodes and the sub-mucosa where they then transfer HIV to CD4 T cells, although there is controversy around this topic. Increases in the levels of the antioxidant glutathione (GSH) plays a critical role in maintaining dendritic cell redox homeostasis, leading to an adequate immune response with sufficient cytokine release and a subsequent robust immune response. Thus, an understanding of the intricate pathways involved in the dendritic cell response are needed to prevent co-infections and co-morbidities in individuals with TB and HIV.

DOCK8-Deficient Mice Reveal a Crucial Role for Dendritic Cell Activity in the Initiation of the Allogeneic Response to Transfused Red Blood Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 658-658
Author(s):  
Stephanie C. Eisenbarth ◽  
Jeanne E. Hendrickson ◽  
Samuele Calabro ◽  
Antonia Gallman
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Innate Immune ◽  
Allogeneic Response ◽  
Deficient Mice

Abstract The generation of antibodies against transfused red blood cells (RBCs) can pose a serious health risk, especially in chronically transfused patients requiring life-long transfusion support; yet our understanding of what immune signals or cells dictate when someone will become alloimmunized is lacking. The relative role of dendritic cells, B cells and macrophages in the induction of RBC alloimmunization remain unclear. Given the now well established role of innate immune signals in regulating adaptive immunity, understanding if and how innate immunity is triggered during transfusion may allow development of therapies to prevent alloimmunization in chronically transfused subjects such as those with myelodysplasia or hemoglobinopathies. We have established a murine model system in which we can evaluate both the role of particular innate immune stimuli as well as particular cells of the immune system in regulating the allogeneic response to transfused RBCs. A particularly useful transgenic "HOD mouse" has been engineered, which encodes a triple fusion protein and provides a unique tool to directly assess both RBC-specific T and B cell responses. This RBC-specific antigen contains the model protein antigen hen egg lysozyme (HEL) fused to chicken ovalbumin (OVA) fused to the human Duffyb blood group antigen (HEL-OVA-Duffy) as an integral membrane protein under control of the beta globin promoter. Transfusion of genetically targeted mice lacking various innate immune cells or receptors allows us to screen for important immune pathways regulating the response to allogeneic RBCs. Using these models, we recently discovered that mice lacking the GEF (guanine nucleotide exchange factor) DOCK8 fail to develop alloimmunity to transfused RBCs. Dendritic cells in these knockout mice fail to migrate to T cells due to lack of coordinated actin rearrangement governed by this GEF. Both B cell and T cell activation in the spleen to the transgenic transfused RBCs is abrogated. Inclusion of OVA in the alloantigen of the HOD mice allows us to readily study naïve CD4+ T cell activation following transfusion by using the OTII T cell receptor (TCR) transgenic mice in which essentially all T cells express one antigen receptor specific for a peptide of OVA. By tracking rounds of cell division we found that adoptively transferred OTII undergo more than 5-8 rounds of division in the spleen three days following transfusion of HOD RBCs in WT recipients. In contrast, no OTII proliferation was observed in DOCK8-deficient mice following OTII adoptive transfer and HOD RBC transfusion, suggesting that T cells are failing to receive activation signals by splenic antigen presenting cells. Our preliminary data now suggest that DOCK8-deficient dendritic cells are able to process and present RBC-derived antigens, but do not migrate to T cell zones in the spleen to prime naïve RBC-specific T cells. The need for dendritic cell migration within the spleen in the induction of alloimmunity to transfused RBCs has not been addressed; these mice allow us for the first time to answer these fundamental immunologic questions during transfusion. Future work will aim to determine how dendritic cell movement within the spleen is regulated during transfusion and the specific role of splenic dendritic cell subsets in CD4+ T cell priming to allogeneic RBCs. Disclosures No relevant conflicts of interest to declare.

Modeling HIV transfer between dendritic cells and T cells: importance of HIV phenotype, dendritic cell– T cell contact and T-cell activation

AIDS ◽  
2000 ◽  
Vol 14 (15) ◽  
pp. 2299-2311 ◽  
Author(s):  
Guido Vanham ◽  
Lieve Penne ◽  
Heidi Allemeersch ◽  
Luc Kestens ◽  
Betty Willems ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Contact

scholarly journals PYR-41 and Thalidomide Impair Dendritic Cell Cross-Presentation by Inhibiting Myddosome Formation and Attenuating the Endosomal Recruitments of p97 and Sec61 via NF-κB Inactivation

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Xiang You ◽  
Dan Dan Xu ◽  
Di Zhang ◽  
Jie Chen ◽  
Feng Guang Gao
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Side Effects ◽  
Protective Immunity ◽  
Therapeutic Effects ◽  
Cross Presentation ◽  
Associated Diseases

PYR-41 and thalidomide have therapeutic effects on inflammation-associated diseases with side effects such as tumorigenesis. Cross-presentation allows dendritic cells (DC) to present endogenous antigen and induce protective immunity against microbe infection and tumors. But, up to now, the effects of PYR-41 and thalidomide on cross-presentation are still uncertain. In this study, we investigated the effect and mechanism of PYR-41 and thalidomide on DC cross-presentation by observing Myddosome formation, endosomal recruitment of p97 and Sec61, NF-κB activation, and cross-priming ability. We demonstrated that the inhibition of endosomal recruitment of p97 and Sec61, together with attenuated NF-κB activation and Myddosome formation, contributes to PYR-41- and thalidomide-impaired cross-presentation and thereby reverses cross-activation of T cells. These observations suggest that NF-κB signaling and p97 and Sec61 molecules are candidates for dealing with the side effects of PYR-41 and thalidomide.

scholarly journals Dendritic cell paucity in mismatch repair–proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy

2021 ◽  
Vol 118 (45) ◽  
pp. e2105323118
Author(s):  
William W. Ho ◽  
Igor L. Gomes-Santos ◽  
Shuichi Aoki ◽  
Meenal Datta ◽  
Kosuke Kawaguchi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Liver Metastasis ◽  
Liver Metastases ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

Liver metastasis is a major cause of mortality for patients with colorectal cancer (CRC). Mismatch repair–proficient (pMMR) CRCs make up about 95% of metastatic CRCs, and are unresponsive to immune checkpoint blockade (ICB) therapy. Here we show that mouse models of orthotopic pMMR CRC liver metastasis accurately recapitulate the inefficacy of ICB therapy in patients, whereas the same pMMR CRC tumors are sensitive to ICB therapy when grown subcutaneously. To reveal local, nonmalignant components that determine CRC sensitivity to treatment, we compared the microenvironments of pMMR CRC cells grown as liver metastases and subcutaneous tumors. We found a paucity of both activated T cells and dendritic cells in ICB-treated orthotopic liver metastases, when compared with their subcutaneous tumor counterparts. Furthermore, treatment with Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 ligand (Flt3L) plus ICB therapy increased dendritic cell infiltration into pMMR CRC liver metastases and improved mouse survival. Lastly, we show that human CRC liver metastases and microsatellite stable (MSS) primary CRC have a similar paucity of T cells and dendritic cells. These studies indicate that orthotopic tumor models, but not subcutaneous models, should be used to guide human clinical trials. Our findings also posit dendritic cells as antitumor components that can increase the efficacy of immunotherapies against pMMR CRC.

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