scholarly journals Th17 T cells and immature dendritic cells are the preferential initial targets after rectal challenge with an SIV-based replication-defective dual-reporter vector

2021 ◽  
Author(s):  
Danijela Maric ◽  
Wesley A. Grimm ◽  
Natalie Greco ◽  
Michael D. McRaven ◽  
Angela J. Fought ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Rectal Mucosa ◽  
Host Cells ◽  
Target Cells ◽  
Receptive Anal Intercourse ◽  
Prevention Strategies ◽  
Immature Dendritic Cells ◽  
Hiv Prevention Strategies ◽  
Dual Reporter

Understanding the earliest events of HIV sexual transmission is critical to develop and optimize HIV prevention strategies. To gain insights into the earliest steps of HIV rectal transmission, including cellular targets, rhesus macaques were intra-rectally challenged with a single-round SIV-based dual reporter that expresses luciferase and iRFP670 upon productive transduction. The vector was pseudotyped with the HIV-1 envelope JRFL. Regions of tissue containing foci of luminescent, transduced cells were identified macroscopically using an in vivo imaging system, and individual transduced cells expressing fluorescent protein were identified and phenotyped microscopically. This system revealed that anal and rectal tissues are both susceptible to transduction 48 hours after the rectal challenge. Detailed phenotypic analysis revealed that on average, 62% of transduced cells are CCR6 + T cells—the vast majority of which express RORγT, a Th17 lineage-specific transcription factor. The second most common target cells were immature dendritic cells at 20%. These two cell types were transduced at the rates that are four to five times higher than their relative abundances indicate. Our work demonstrates that Th17 T and immature dendritic cells are preferential initial targets of HIV/SIV rectal transmission. IMPORTANCE Men and women who participate in unprotected receptive anal intercourse are at high risk for acquiring HIV. While in vitro data have developed a framework for understanding HIV cell tropism, the initial target cells in the rectal mucosa have not been identified. In this study, we identify these early host cells by using an innovative rhesus macaque rectal challenge model and methodology, which we previously developed. Thus, by shedding light on these early HIV/SIV transmission events, this study provides a specific cellular target for future prevention strategies.

scholarly journals Th17 T cells and immature dendritic cells are the preferential initial targets after rectal challenge with an SIV-based replication-defective dual-reporter vector

2021 ◽  
Author(s):  
Danijela Maric ◽  
Wesley A. Grimm ◽  
Natalie Greco ◽  
Michael D. McRaven ◽  
Angela J. Fought ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Rectal Mucosa ◽  
Host Cells ◽  
Target Cells ◽  
Receptive Anal Intercourse ◽  
Prevention Strategies ◽  
Immature Dendritic Cells ◽  
Hiv Prevention Strategies ◽  
Dual Reporter

ABSTRACTUnderstanding the earliest events of HIV sexual transmission is critical to develop and optimize HIV prevention strategies. To gain insights into the earliest steps of HIV rectal transmission, including cellular targets, rhesus macaques were intra-rectally challenged with a single-round SIV-based dual reporter that expresses luciferase and iRFP670 upon productive transduction. The vector was pseudotyped with the HIV-1 envelope JRFL. Regions of tissue containing foci of luminescent, transduced cells were identified macroscopically using an in vivo imaging system, and individual transduced cells expressing fluorescent protein were identified and phenotyped microscopically. This system revealed that anal and rectal tissues are both susceptible to transduction 48 hours after the rectal challenge. Detailed phenotypic analysis revealed that on average, 62% of transduced cells are CCR6+ T cells—the vast majority of which express RORγT, a Th17 lineage-specific transcription factor. The second most common target cells were immature dendritic cells at 20%. These two cell types were transduced at the rates that are four to five times higher than their relative abundances indicate. Our work demonstrates that Th17 T and immature dendritic cells are preferential initial targets of HIV/SIV rectal transmission.IMPORTANCEMen and women who participate in unprotected receptive anal intercourse are at high risk for acquiring HIV. While in vitro data have developed a framework for understanding HIV cell tropism, the initial target cells in the rectal mucosa have not been identified. In this study, we identify these early host cells by using an innovative rhesus macaque rectal challenge model and methodology, which we previously developed. Thus, by shedding light on these early HIV/SIV transmission events, this study provides a specific cellular target for future prevention strategies.

scholarly journals Human anogenital monocyte-derived dendritic cells and langerin+cDC2 are major HIV target cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jake W. Rhodes ◽  
Rachel A. Botting ◽  
Kirstie M. Bertram ◽  
Erica E. Vine ◽  
Hafsa Rana ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Pathogen Detection ◽  
Hiv Transmission ◽  
Sexual Transmission ◽  
Mononuclear Phagocytes ◽  
Target Cells ◽  
Epithelial Surface ◽  
Transmission Studies

AbstractTissue mononuclear phagocytes (MNP) are specialised in pathogen detection and antigen presentation. As such they deliver HIV to its primary target cells; CD4 T cells. Most MNP HIV transmission studies have focused on epithelial MNPs. However, as mucosal trauma and inflammation are now known to be strongly associated with HIV transmission, here we examine the role of sub-epithelial MNPs which are present in a diverse array of subsets. We show that HIV can penetrate the epithelial surface to interact with sub-epithelial resident MNPs in anogenital explants and define the full array of subsets that are present in the human anogenital and colorectal tissues that HIV may encounter during sexual transmission. In doing so we identify two subsets that preferentially take up HIV, become infected and transmit the virus to CD4 T cells; CD14+CD1c+ monocyte-derived dendritic cells and langerin-expressing conventional dendritic cells 2 (cDC2).

scholarly journals 714 Selective expansion of antigen-specific CD8 T cells with engineered antigen presenting exosome

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A743-A743
Author(s):  
Tomoyoshi Yamano ◽  
Xiabing Lyu ◽  
Rikinari Hanayama
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd8 T Cells ◽  
Costimulatory Molecule ◽  
Animal Experiments ◽  
Surface Proteins ◽  
Hek293 Cells ◽  
Target Cells ◽  
Single Chain ◽  
Antigen Presenting

BackgroundExosomes are vesicular granules of about 100 nm and are secreted by many types of cells. Exosomes contain various proteins, lipids, and RNAs that are transported to target cells which induce functional and physiological changes. Exosomes are promising nano-vesicles for clinical application, owing to their high biocompatibility, low immunogenicity, and high drug delivery efficacy. Recent studies have demonstrated that exosomes from tumor cells or antigen presenting cells (APCs) regulate immune responses. Tumor derived exosomes express PD-L1 on their surface and suppress tumor immunity systemically. On the other hand, mature dendritic cells derived exosomes exert immune activation, and tumor immunotherapy using DCs exosome has been developed. However, few studies have been found to exert a significant effect on cancer treatment, may be because of low expression of costimulatory molecules and lack of cytokines on DCs derived exosomes.MethodsIt has been demonstrated that GFP can be conveyed into exosomes by conjugating GFP with tetraspanins, exosome-specific surface proteins. First, we generated a tetraspanin fusion protein with a single-chain MHCI trimer (scMHCI). IL-2 is inserted on the second extracellular loop of CD81, allowing robust and functional expression of IL-2 on the exosome. We collected exosomes from HEK293 cells culture, which stably express scMHCI-CD81-IL2 and CD80-MFGE8, and used as Antigen-presenting exosome(AP-Exo).ResultsAP-Exo expresses high expression of MHCI-peptide complex, costimulatory molecule, and cytokine, activating cognate CD8 T cells as dendritic cells do. AP-Exo selectively delivered co-stimulation and IL-2 to antigen-specific CD8 T cells, resulting in a massive expansion of antigen-specific CD8 T cells without severe adverse effects in mice. AP-Exo can expand endogenous tumor-specific CD8 T cells and induce the potent anti-tumor effect.ConclusionsOur strategy for building engineered exosomes that work like APCs might develop novel methods for cancer immunotherapy.Ethics ApprovalAll mice were housed in a specific pathogen-free facility, and all animal experiments were performed according to a protocol approved by Kanazawa University, Kanazawa, Japan.

scholarly journals Generation of Human CD8 T Regulatory Cells by CD40 Ligand–activated Plasmacytoid Dendritic Cells

2002 ◽  
Vol 195 (6) ◽  
pp. 695-704 ◽  
Author(s):  
Michel Gilliet ◽  
Yong-Jun Liu
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Transforming Growth Factor ◽  
Cd8 T Cell ◽  
Cd40 Ligand ◽  
Plasmacytoid Dendritic Cells ◽  
Target Cells ◽  
Ifn Γ

Although CD8 T cell–mediated immunosuppression has been a well-known phenomenon during the last three decades, the nature of primary CD8 T suppressor cells and the mechanism underlying their generation remain enigmatic. We demonstrated that naive CD8 T cells primed with allogeneic CD40 ligand–activated plasmacytoid dendritic cells (DC)2 differentiated into CD8 T cells that displayed poor secondary proliferative and cytolytic responses. By contrast, naive CD8 T cells primed with allogeneic CD40 ligand–activated monocyte-derived DCs (DC1) differentiated into CD8 T cells, which proliferated to secondary stimulation and killed allogeneic target cells. Unlike DC1-primed CD8 T cells that produced large amounts of interferon (IFN)-γ upon restimulation, DC2-primed CD8 T cells produced significant amounts of interleukin (IL)-10, low IFN-γ, and no IL-4, IL-5, nor transforming growth factor (TGF)-β. The addition of anti–IL-10–neutralizing monoclonal antibodies during DC2 and CD8 T cell coculture, completely blocked the generation of IL-10–producing anergic CD8 T cells. IL-10–producing CD8 T cells strongly inhibit the allospecific proliferation of naive CD8 T cells to monocytes, and mature and immature DCs. This inhibition was mediated by IL-10, but not by TGF-β. IL-10–producing CD8 T cells could inhibit the bystander proliferation of naive CD8 T cells, provided that they were restimulated nearby to produce IL-10. IL-10–producing CD8 T cells could not inhibit the proliferation of DC1-preactivated effector T cells. This study demonstrates that IL-10–producing CD8 T cells are regulatory T cells, which provides a cellular basis for the phenomenon of CD8 T cell–mediated immunosuppression and suggests a role for plasmacytoid DC2 in immunological tolerance.

scholarly journals Spinophilin and the immune synapse

2008 ◽  
Vol 181 (2) ◽  
pp. 181-183 ◽  
Author(s):  
Brian Seed ◽  
Ramnik Xavier
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Fusion Protein ◽  
Target Cells ◽  
Cellular Organization ◽  
Immune Synapse ◽  
Cellular Architecture ◽  
Gfp Fusion Protein ◽  
Cell Biol ◽  
In Cells

Extensive alterations in cellular organization are known to accompany the responses of sensitized T cells to target cells presenting an antigen of interest. Now, equally if not more dramatic changes are found to take place in cells presenting an antigen. With the help of a spinophilin-GFP fusion protein, Bloom et al. (Bloom, O., J.J. Unternaehrer, A. Jiang, J.-S. Shin, L. Delamarre, P. Allen, and I. Mellman. 2008. J. Cell Biol. 181:203–211) have captured a remarkable polarization of the cellular architecture of dendritic cells presenting an antigen to T cells.

scholarly journals Immature dendritic cells convert anergic nonregulatory T cells into Foxp3−IL-10+regulatory T cells by engaging CD28 and CTLA-4

2014 ◽  
Vol 45 (2) ◽  
pp. 480-491 ◽  
Author(s):  
Katrien Pletinckx ◽  
Martin Vaeth ◽  
Theresa Schneider ◽  
Niklas Beyersdorf ◽  
Thomas Hünig ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Regulatory T Cells ◽  
Immature Dendritic Cells

Stimulation of cytotoxic T cells against idiotype immunoglobulin of malignant lymphoma with protein-pulsed or idiotype-transduced dendritic cells

Blood ◽  
2000 ◽  
Vol 95 (4) ◽  
pp. 1342-1349 ◽  
Author(s):  
Frank Osterroth ◽  
Annette Garbe ◽  
Paul Fisch ◽  
Hendrik Veelken
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Light Chain ◽  
Cytotoxic T Cells ◽  
Killer Cell ◽  
Cell Activity ◽  
Expression Vectors ◽  
Target Cells ◽  
Fab Fragment ◽  
Specific Lysis

Because of their hypervariable regions and somatic mutations, the antigen receptor molecules of lymphomas (idiotypes) are tumor-specific antigens and attractive targets for antilymphoma immunotherapy. For the optimal induction of human idiotype-specific cytotoxic T cells (CTL), idiotype was presented to CD8+ peripheral blood mononuclear cells by monocyte-derived autologous dendritic cells (DC) after the endocytosis of idiotype protein or by idiotype-expressing DC. Recombinant idiotype was obtained as a functionally folded Fab fragment by periplasmic expression in Escherichia coli. Idiotype-expressing DC were generated by transduction with recombinant Semliki forest virus vectors encompassing heavy- or light-chain idiotype genes. Autologous lymphoblastoid cell lines stably transfected with Epstein-Barr virus-based idiotype expression vectors were used as target cells to detect idiotype-specific lysis. CTL stimulated with idiotype-loaded DC showed strong specific, CD8-mediated, and major histocompatibility complex (MHC) class I-restricted cytotoxicity against autologous heavy- and light-chain idiotype. In contrast, stimulation with idiotype-transduced DC resulted in only moderate natural killer cell activity. These data confirm the existence of idiotype-specific CTL in patients with lymphoma, define a “good manufacturing practice”-compatible protocol for the generation of these cells without the requirement of viable lymphoma cells, and favor the processing of exogenous antigen over DC transduction for the induction of MHC I-restricted CTL against idiotypes with unknown antigenicity.

β-Defensins: Linking Innate and Adaptive Immunity Through Dendritic and T Cell CCR6

Science ◽  
1999 ◽  
Vol 286 (5439) ◽  
pp. 525-528 ◽  
Author(s):  
D. Yang ◽  
O. Chertov ◽  
S. N. Bykovskaia ◽  
Q. Chen ◽  
M. J. Buffo ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Cytoplasmic Membrane ◽  
Memory T Cells ◽  
Innate And Adaptive Immunity ◽  
Adaptive Immune ◽  
Microbial Invasion ◽  
Immature Dendritic Cells ◽  
Chemokine Ligand

Defensins contribute to host defense by disrupting the cytoplasmic membrane of microorganisms. This report shows that human β-defensins are also chemotactic for immature dendritic cells and memory T cells. Human β-defensin was selectively chemotactic for cells stably transfected to express human CCR6, a chemokine receptor preferentially expressed by immature dendritic cells and memory T cells. The β-defensin–induced chemotaxis was sensitive to pertussis toxin and inhibited by antibodies to CCR6. The binding of iodinated LARC, the chemokine ligand for CCR6, to CCR6-transfected cells was competitively displaced by β-defensin. Thus, β-defensins may promote adaptive immune responses by recruiting dendritic and T cells to the site of microbial invasion through interaction with CCR6.

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