scholarly journals Targeting self- and foreign antigens to dendritic cells via DC-ASGPR generates IL-10–producing suppressive CD4+ T cells

2012 ◽  
Vol 209 (1) ◽  
pp. 109-121 ◽  
Author(s):  
Dapeng Li ◽  
Gabrielle Romain ◽  
Anne-Laure Flamar ◽  
Dorothée Duluc ◽  
Melissa Dullaers ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Oxidized Ldl ◽  
Scavenger Receptor ◽  
Ldl Receptor ◽  
Interleukin 10 ◽  
Protein Antigens ◽  
Host Immune Responses

Dendritic cells (DCs) can initiate and shape host immune responses toward either immunity or tolerance by their effects on antigen-specific CD4+ T cells. DC-asialoglycoprotein receptor (DC-ASGPR), a lectinlike receptor, is a known scavenger receptor. Here, we report that targeting antigens to human DCs via DC-ASGPR, but not lectin-like oxidized-LDL receptor, Dectin-1, or DC-specific ICAM-3–grabbing nonintegrin favors the generation of antigen-specific suppressive CD4+ T cells that produce interleukin 10 (IL-10). These findings apply to both self- and foreign antigens, as well as memory and naive CD4+ T cells. The generation of such IL-10–producing CD4+ T cells requires p38/extracellular signal-regulated kinase phosphorylation and IL-10 induction in DCs. We further demonstrate that immunization of nonhuman primates with antigens fused to anti–DC-ASGPR monoclonal antibody generates antigen-specific CD4+ T cells that produce IL-10 in vivo. This study provides a new strategy for the establishment of antigen-specific IL-10–producing suppressive T cells in vivo by targeting whole protein antigens to DCs via DC-ASGPR.

scholarly journals CD4+ T Cells Elicit Host Immune Responses to MHC Class II− Ovarian Cancer through CCL5 Secretion and CD40-Mediated Licensing of Dendritic Cells

2010 ◽  
Vol 184 (10) ◽  
pp. 5654-5662 ◽  
Author(s):  
Yolanda C. Nesbeth ◽  
Diana G. Martinez ◽  
Seiko Toraya ◽  
Uciane K. Scarlett ◽  
Juan R. Cubillos-Ruiz ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Host Immune Responses

scholarly journals Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance

2017 ◽  
Vol 114 (5) ◽  
pp. 1099-1104 ◽  
Author(s):  
William Bracamonte-Baran ◽  
Jonathan Florentin ◽  
Ying Zhou ◽  
Ewa Jankowska-Gan ◽  
W. John Haynes ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Extracellular Vesicle ◽  
Membrane Microdomains ◽  
Transplant Tolerance ◽  
Split Tolerance ◽  
Cross Dressing

Maternal microchimerism (MMc) has been associated with development of allospecific transplant tolerance, antitumor immunity, and cross-generational reproductive fitness, but its mode of action is unknown. We found in a murine model that MMc caused exposure to the noninherited maternal antigens in all offspring, but in some, MMc magnitude was enough to cause membrane alloantigen acquisition (mAAQ; “cross-dressing”) of host dendritic cells (DCs). Extracellular vesicle (EV)-enriched serum fractions from mAAQ+, but not from non-mAAQ, mice reproduced the DC cross-dressing phenomenon in vitro. In vivo, mAAQ was associated with increased expression of immune modulators PD-L1 (programmed death-ligand 1) and CD86 by myeloid DCs (mDCs) and decreased presentation of allopeptide+self-MHC complexes, along with increased PD-L1, on plasmacytoid DCs (pDCs). Remarkably, both serum EV-enriched fractions and membrane microdomains containing the acquired MHC alloantigens included CD86, but completely excluded PD-L1. In contrast, EV-enriched fractions and microdomains containing allopeptide+self-MHC did not exclude PD-L1. Adoptive transfer of allospecific transgenic CD4 T cells revealed a “split tolerance” status in mAAQ+mice: T cells recognizing intact acquired MHC alloantigens proliferated, whereas those responding to allopeptide+self-MHC did not. Using isolated pDCs and mDCs for in vitro culture with allopeptide+self-MHC–specific CD4 T cells, we could replicate their normal activation in non-mAAQ mice, and PD-L1–dependent anergy in mAAQ+hosts. We propose that EVs provide a physiologic link between microchimerism and split tolerance, with implications for tumor immunity, transplantation, autoimmunity, and reproductive success.

scholarly journals Interleukin-10-Treated Dendritic Cells Modulate Immune Responses of Naive and Sensitized T Cells In Vivo

2002 ◽  
Vol 119 (4) ◽  
pp. 836-841 ◽  
Author(s):  
Gabriele Müller ◽  
Anke Müller ◽  
Thomas Tüting ◽  
Kerstin Steinbrink ◽  
Joachim Saloga ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Interleukin 10

scholarly journals Direct Expansion of Functional CD25+ CD4+ Regulatory T Cells by Antigen-processing Dendritic Cells

2003 ◽  
Vol 198 (2) ◽  
pp. 235-247 ◽  
Author(s):  
Sayuri Yamazaki ◽  
Tomonori Iyoda ◽  
Kristin Tarbell ◽  
Kara Olson ◽  
Klara Velinzon ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Antigen Processing ◽  
Specific Antigen ◽  
Cell Receptor ◽  
Cd4 T Cell

An important pathway for immune tolerance is provided by thymic-derived CD25+ CD4+ T cells that suppress other CD25− autoimmune disease–inducing T cells. The antigen-presenting cell (APC) requirements for the control of CD25+ CD4+ suppressor T cells remain to be identified, hampering their study in experimental and clinical situations. CD25+ CD4+ T cells are classically anergic, unable to proliferate in response to mitogenic antibodies to the T cell receptor complex. We now find that CD25+ CD4+ T cells can proliferate in the absence of added cytokines in culture and in vivo when stimulated by antigen-loaded dendritic cells (DCs), especially mature DCs. With high doses of DCs in culture, CD25+ CD4+ and CD25− CD4+ populations initially proliferate to a comparable extent. With current methods, one third of the antigen-reactive T cell receptor transgenic T cells enter into cycle for an average of three divisions in 3 d. The expansion of CD25+ CD4+ T cells stops by day 5, in the absence or presence of exogenous interleukin (IL)-2, whereas CD25− CD4+ T cells continue to grow. CD25+ CD4+ T cell growth requires DC–T cell contact and is partially dependent upon the production of small amounts of IL-2 by the T cells and B7 costimulation by the DCs. After antigen-specific expansion, the CD25+ CD4+ T cells retain their known surface features and actively suppress CD25− CD4+ T cell proliferation to splenic APCs. DCs also can expand CD25+ CD4+ T cells in the absence of specific antigen but in the presence of exogenous IL-2. In vivo, both steady state and mature antigen-processing DCs induce proliferation of adoptively transferred CD25+ CD4+ T cells. The capacity to expand CD25+ CD4+ T cells provides DCs with an additional mechanism to regulate autoimmunity and other immune responses.

Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3249-3256 ◽  
Author(s):  
Laurence Weiss ◽  
Vladimira Donkova-Petrini ◽  
Laure Caccavelli ◽  
Michèle Balbo ◽  
Cédric Carbonneil ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Highly Active Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Cell Subset ◽  
Transforming Growth Factor Β ◽  
Interleukin 10

Abstract The present study demonstrates that CD4+CD25+ T cells, expanded in peripheral blood of HIV-infected patients receiving highly active antiretroviral therapy (HAART), exhibit phenotypic, molecular, and functional characteristics of regulatory T cells. The majority of peripheral CD4+CD25+ T cells from HIV-infected patients expressed a memory phenotype. They were found to constitutively express transcription factor forkhead box P3 (Foxp3) messengers. CD4+CD25+ T cells weakly proliferated to immobilized anti-CD3 monoclonal antibody (mAb) and addition of soluble anti-CD28 mAb significantly increased proliferation. In contrast to CD4+CD25– T cells, CD4+CD25+ T cells from HIV-infected patients did not proliferate in response to recall antigens and to p24 protein. The proliferative capacity of CD4 T cells to tuberculin, cytomegalovirus (CMV), and p24 significantly increased following depletion of CD4+CD25+ T cells. Furthermore, addition of increasing numbers of CD4+CD25+ T cells resulted in a dose-dependent inhibition of CD4+CD25– T-cell proliferation to tuberculin and p24. CD4+CD25+ T cells responded specifically to p24 antigen stimulation by expressing transforming growth factor β (TGF-β) and interleukin 10 (IL-10), thus indicating the presence of p24-specific CD4+ T cells among the CD4+CD25+ T-cell subset. Suppressive activity was not dependent on the secretion of TGF-β or IL-10. Taken together, our results suggest that persistence of HIV antigens might trigger the expansion of CD4+CD25+ regulatory T cells, which might induce a tolerance to HIV in vivo.

scholarly journals Dendritic cells are the principal cells in mouse spleen bearing immunogenic fragments of foreign proteins.

1990 ◽  
Vol 172 (1) ◽  
pp. 383-386 ◽  
Author(s):  
M Crowley ◽  
K Inaba ◽  
R M Steinman
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Peritoneal Cavity ◽  
Peptide Fragments ◽  
Cell Type ◽  
Protein Antigens ◽  
Main Cell ◽  
Foreign Proteins ◽  
Main Cell Type

We monitored the APC function of cells taken from the spleen and peritoneal cavity of mice that had been given protein antigens via the intravenous or intraperitoneal routes. Using the mAb 33D1 and N418 to negatively and positively select dendritic cells, we obtained evidence that dendritic cells are the main cell type in spleen that carries the protein in a form that is immunogenic for antigen-specific T cells. In vivo pulsed macrophages were not immunogenic and did not appear capable of transferring peptide fragments to dendritic cells.

scholarly journals Virus-stimulated plasmacytoid dendritic cells induce CD4+ cytotoxic regulatory T cells

Blood ◽  
2006 ◽  
Vol 107 (3) ◽  
pp. 1031-1038 ◽  
Author(s):  
Kazuko Kawamura ◽  
Norimitsu Kadowaki ◽  
Toshio Kitawaki ◽  
Takashi Uchiyama
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Regulatory T Cells ◽  
Cd4 T Cells ◽  
Inflammatory Responses ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Plasmacytoid Dendritic Cells ◽  
Dependent Manner ◽  
Persistent Viral Infection

AbstractImmune responses to pathogens need to be maintained within appropriate levels to minimize tissue damage, whereas such controlled immunity may allow persistent infection of certain types of pathogens. Interleukin 10 (IL-10) plays an important role in such immune regulation. We previously showed that HSV-stimulated human plasmacytoid dendritic cells (pDCs) induced naive CD4+ T cells to differentiate into interferon γ (IFN-γ)/IL-10–producing T cells. Here we show that HSV-stimulated pDCs induce allogeneic naive CD4+ T cells to differentiate into cytotoxic regulatory T cells that poorly proliferate on restimulation and inhibit proliferation of coexisting naive CD4+ T cells. IL-3–stimulated pDCs or myeloid DCs did not induce such regulatory T cells. Both IFN-α and IL-10 were responsible for the induction of anergic and regulatory properties. High percentages of CD4+ T cells cocultured with HSV-stimulated pDCs, and to a lesser extent those cocultured with IL-3–stimulated pDCs, expressed granzyme B and perforin in an IL-10–dependent manner. CD4+ T cells cocultured with HSV-stimulated pDCs accordingly exhibited cytotoxic activity. The finding that virus-stimulated pDCs are capable of inducing CD4+ cytotoxic regulatory T cells suggests that this DC subset may play an important role in suppressing excessive inflammatory responses and also in inducing persistent viral infection.

scholarly journals Dendritic cells, but not macrophages or B cells, activate major histocompatibility complex class II-restricted CD4+T cells upon immune-complex uptake in vivo

Immunology ◽  
2006 ◽  
Vol 119 (4) ◽  
pp. 499-506 ◽  
Author(s):  
Judith M. H. de Jong ◽  
Danita H. Schuurhuis ◽  
Andreea Ioan-Facsinay ◽  
Mick M. Welling ◽  
Marcel G. M. Camps ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Major Histocompatibility Complex ◽  
B Cells ◽  
Major Histocompatibility Complex Class ◽  
Immune Complex ◽  
Cd4 T Cells ◽  
Complex Class ◽  
Histocompatibility Complex

scholarly journals Complex Carbohydrates Are Not Removed During Processing of Glycoproteins by Dendritic Cells

2002 ◽  
Vol 196 (11) ◽  
pp. 1435-1446 ◽  
Author(s):  
Anda M. Vlad ◽  
Stefan Muller ◽  
Mare Cudic ◽  
Hans Paulsen ◽  
Laszlo Otvos ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Mhc Class Ii ◽  
Major Histocompatability Complex ◽  
Protein Antigens ◽  
Acidic Compartments ◽  
Shed Light ◽  
Mhc Class Ii Molecules

In contrast to protein antigens, processing of glycoproteins by dendritic cells (DCs) for presentation to T cells has not been well studied. We developed mouse T cell hybridomas to study processing and presentation of the tumor antigen MUC1 as a model glycoprotein. MUC1 is expressed on the surface as well as secreted by human adenocarcinomas. Circulating soluble MUC1 is available for uptake, processing, and presentation by DCs in vivo and better understanding of how that process functions in the case of glycosylated antigens may shed light on antitumor immune responses that could be initiated against this glycoprotein. We show that DCs endocytose MUC1 glycopeptides, transport them to acidic compartments, process them into smaller peptides, and present them on major histocompatability complex (MHC) class II molecules without removing the carbohydrates. Glycopeptides that are presented on DCs are recognized by T cells. This suggests that a much broader repertoire of T cells could be elicited against MUC1 and other glycoproteins than expected based only on their peptide sequences.

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