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

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.

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CD4+ CD25+ Regulatory T Cells Control T Helper Cell Type 1 Responses to Foreign Antigens Induced by Mature Dendritic Cells In Vivo

Journal of Experimental Medicine ◽

10.1084/jem.20030654 ◽

2003 ◽

Vol 198 (2) ◽

pp. 259-266 ◽

Cited By ~ 169

Author(s):

Guillaume Oldenhove ◽

Magali de Heusch ◽

Georgette Urbain-Vansanten ◽

Jacques Urbain ◽

Charlie Maliszewski ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Regulatory T Cells ◽

Immune Responses ◽

Peripheral Tolerance ◽

T Helper Cell ◽

Helper Cell ◽

T Helper

Recent evidence suggests that in addition to their well known stimulatory properties, dendritic cells (DCs) may play a major role in peripheral tolerance. It is still unclear whether a distinct subtype or activation status of DC exists that promotes the differentiation of suppressor rather than effector T cells from naive precursors. In this work, we tested whether the naturally occurring CD4+ CD25+ regulatory T cells (Treg) may control immune responses induced by DCs in vivo. We characterized the immune response induced by adoptive transfer of antigen-pulsed mature DCs into mice depleted or not of CD25+ cells. We found that the development of major histocompatibility complex class I and II–restricted interferon γ–producing cells was consistently enhanced in the absence of Treg. By contrast, T helper cell (Th)2 priming was down-regulated in the same conditions. This regulation was independent of interleukin 10 production by DCs. Of note, splenic DCs incubated in vitro with Toll-like receptor ligands (lipopolysaccharide or CpG) activated immune responses that remained sensitive to Treg function. Our data further show that mature DCs induced higher cytotoxic activity in CD25-depleted recipients as compared with untreated hosts. We conclude that Treg naturally exert a negative feedback mechanism on Th1-type responses induced by mature DCs in vivo.

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Anti-CD40 Antibody Fused to CD40 Ligand Is a Superagonist Platform for Adjuvant Intrinsic DC-Targeting Vaccines

Frontiers in Immunology ◽

10.3389/fimmu.2021.786144 ◽

2022 ◽

Vol 12 ◽

Author(s):

Valentina Ceglia ◽

Sandra Zurawski ◽

Monica Montes ◽

Mitchell Kroll ◽

Aurélie Bouteau ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Immune Responses ◽

Class I ◽

Agonist Activity ◽

Cell Immunity ◽

Hiv 1

CD40 is a potent activating receptor expressed on antigen-presenting cells (APCs) of the immune system. CD40 regulates many aspects of B and T cell immunity via interaction with CD40L expressed on activated T cells. Targeting antigens to CD40 via agonistic anti-CD40 antibody fusions promotes both humoral and cellular immunity, but current anti-CD40 antibody-antigen vaccine prototypes require co-adjuvant administration for significant in vivo efficacy. This may be a consequence of dulling of anti-CD40 agonist activity via antigen fusion. We previously demonstrated that direct fusion of CD40L to anti-CD40 antibodies confers superagonist properties. Here we show that anti-CD40-CD40L-antigen fusion constructs retain strong agonist activity, particularly for activation of dendritic cells (DCs). Therefore, we tested anti-CD40-CD40L antibody fused to antigens for eliciting immune responses in vitro and in vivo. In PBMC cultures from HIV-1-infected donors, anti-CD40-CD40L fused to HIV-1 antigens preferentially expanded HIV-1-specific CD8+ T cells versus CD4+ T cells compared to analogous anti-CD40-antigen constructs. In normal donors, anti-CD40-CD40L-mediated delivery of Influenza M1 protein elicited M1-specific T cell expansion at lower doses compared to anti-CD40-mediated delivery. Also, on human myeloid-derived dendritic cells, anti-CD40-CD40L-melanoma gp100 peptide induced more sustained Class I antigen presentation compared to anti-CD40-gp100 peptide. In human CD40 transgenic mice, anti-CD40-CD40L-HIV-1 gp140 administered without adjuvant elicited superior antibody responses compared to anti-CD40-gp140 antigen without fused CD40L. In human CD40 mice, compared to the anti-CD40 vehicle, anti-CD40-CD40L delivery of Eα 52-68 peptide elicited proliferating of TCR I-Eα 52-68 CD4+ T cells producing cytokine IFNγ. Also, compared to controls, only anti-CD40-CD40L-Cyclin D1 vaccination of human CD40 mice reduced implanted EO771.LMB breast tumor cell growth. These data demonstrate that human CD40-CD40L antibody fused to antigens maintains highly agonistic activity and generates immune responses distinct from existing low agonist anti-CD40 targeting formats. These advantages were in vitro skewing responses towards CD8+ T cells, increased efficacy at low doses, and longevity of MHC Class I peptide display; and in mouse models, a more robust humoral response, more activated CD4+ T cells, and control of tumor growth. Thus, the anti-CD40-CD40L format offers an alternate DC-targeting platform with unique properties, including intrinsic adjuvant activity.

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Altered Immune Responses in Interleukin 10 Transgenic Mice

Journal of Experimental Medicine ◽

10.1084/jem.185.12.2101 ◽

1997 ◽

Vol 185 (12) ◽

pp. 2101-2110 ◽

Cited By ~ 196

Author(s):

Amy Hagenbaugh ◽

Sherven Sharma ◽

Steven M. Dubinett ◽

Sherry H.-Y. Wei ◽

Richard Aranda ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

Immune Responses ◽

Leishmania Major ◽

Severe Combined Immunodeficiency ◽

Interleukin 10 ◽

Altered Expression

Interleukin (IL)-10 is a pleiotropic cytokine which inhibits a broad array of immune parameters including T helper cell type 1 (Th1) cytokine production, antigen presentation, and antigenspecific T cell proliferation. To understand the consequences of altered expression of IL-10 in immune models of autoimmune disease, the response to infectious agents, and the response to tumors, we developed transgenic mice expressing IL-10 under the control of the IL-2 promoter. Upon in vitro stimulation, spleen cells from unimmunized transgenic mice secrete higher levels of IL-10 and lower amounts of IFN-γ than do controls, although no gross abnormalities were detected in lymphocyte populations or serum Ig levels. Transfer of normally pathogenic CD4+ CD45RBhigh splenic T cells from IL-10 transgenic mice did not cause colitis in recipient severe combined immunodeficiency mice. Furthermore, co-transfer of these transgenic cells with CD4+ CD45RBhigh T cells from control mice prevented disease. Transgenic mice retained their resistance to Leishmania major infection, indicating that their cell-mediated immune responses were not globally suppressed. Lastly, in comparison to controls, IL-10 transgenic mice were unable to limit the growth of immunogenic tumors. Administration of blocking IL-10 mAbs restored in vivo antitumor responses in the transgenic mice. These results demonstrate that a single alteration in the T cell cytokine profile can lead to dramatic changes in immune responses in a manner that is stimulus dependent. These mice will be useful in defining differences in inflammatory conditions and cellular immunity mediated by IL-10.

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

Journal of Experimental Medicine ◽

10.1084/jem.20020493 ◽

2002 ◽

Vol 196 (11) ◽

pp. 1435-1446 ◽

Cited By ~ 103

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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Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo

Journal of Experimental Medicine ◽

10.1084/jem.20050783 ◽

2006 ◽

Vol 203 (3) ◽

pp. 505-511 ◽

Cited By ~ 356

Author(s):

Carlos E. Tadokoro ◽

Guy Shakhar ◽

Shiqian Shen ◽

Yi Ding ◽

Andreia C. Lino ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Regulatory T Cells ◽

Immune Responses ◽

Lymph Nodes ◽

Laser Scanning ◽

Laser Scanning Microscopy ◽

Early Effect ◽

Two Photon

Regulatory T (T reg) cells exert powerful down-modulatory effects on immune responses, but it is not known how they act in vivo. Using intravital two-photon laser scanning microscopy we determined that, in the absence of T reg cells, the locomotion of autoantigen-specific T cells inside lymph nodes is decreased, and the contacts between T cells and antigen-loaded dendritic cells (DCs) are of longer duration. Thus, T reg cells can exert an early effect on immune responses by attenuating the establishment of stable contacts during priming of naive T cells by DCs.

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Stimulation of Dendritic Cells via CD40 Enhances Immune Responses to Mycobacterium tuberculosisInfection

Infection and Immunity ◽

10.1128/iai.69.4.2456-2461.2001 ◽

2001 ◽

Vol 69 (4) ◽

pp. 2456-2461 ◽

Cited By ~ 43

Author(s):

Caroline Demangel ◽

Umaimainthan Palendira ◽

Carl G. Feng ◽

Andrew W. Heath ◽

Andrew G. D. Bean ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Immune Responses ◽

Protective Efficacy ◽

Interleukin 12 ◽

Ifn Γ ◽

Cellular Immune ◽

Stimulation Of

ABSTRACT The resolution of pulmonary tuberculosis (TB) critically depends on the development of the Th1 type of immune responses, as exemplified by the exacerbation of TB in IL-12-deficient mice. Therefore, vaccination strategies optimizing IL-12 production by antigen-presenting cells (APC) in response to mycobacteria may have enhanced protective efficacy. Since dendritic cells (DC) are the critical APC for activation of CD4+ and CD8+ T cells, we examined whether stimulation of Mycobacterium bovis bacillus Calmette Guérin (BCG)-infected DC via CD40 increased their ability to generate Th1-oriented cellular immune responses. Incubation of DC with an agonistic anti-CD40 antibody activated CD40 signaling in DC, as shown by increased expression of major histocompatibility complex class II and costimulatory molecules, mRNA production for proinflammatory cytokines and interleukin 12 (IL-12) p40. This activation pattern was maintained when DC were stimulated with anti-CD40 antibody and infected with BCG. Importantly, CD40-stimulated BCG-infected DC displayed increased capacity to release bioactive IL-12 and to activate gamma interferon (IFN-γ) producing T cells in vitro. Moreover, when C57BL/6 mice were immunized with these DC and challenged with aerosol Mycobacterium tuberculosis, increased levels of mRNA for IL-12 p40, IL-18, and IFN-γ were present in the draining mediastinal lymph nodes. However, the mycobacterial burden in the lungs was not reduced compared to that in mice immunized with BCG-infected non-CD40-stimulated DC. Therefore, although the manipulation of DC via CD40 is effective for enhancing immune responses to mycobacteria in vivo, additional strategies are required to increase protection against virulent M. tuberculosis infection.

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Circulating blood dendritic cells from myeloid leukemia patients display quantitative and cytogenetic abnormalities as well as functional impairment

Blood ◽

10.1182/blood.v98.13.3750 ◽

2001 ◽

Vol 98 (13) ◽

pp. 3750-3756 ◽

Cited By ~ 124

Author(s):

Mohamad Mohty ◽

David Jarrossay ◽

Marina Lafage-Pochitaloff ◽

Christine Zandotti ◽

Francine Brière ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Immune Responses ◽

Myeloid Leukemia ◽

Ex Vivo ◽

Interferon Α ◽

Immune Control ◽

Myeloid Leukemias ◽

Acute Myeloid

Abstract Dendritic cells (DCs) are responsible for the initiation of immune responses. Two distinct subsets of blood DCs have been characterized thus far. Myeloid DCs (MDCs) and plasmacytoid monocytes (PDCs) were shown to be able to promote polarization of naive T cells. This study shows a dramatic quantitative imbalance in both circulating blood DC subsets in 37 patients with acute myeloid leukemias. Eleven patients (30%) displayed a normal quantitative profile (MDC mean, 0.37% ± 0.21%; range, 0.01% to 0.78%; PDC mean, 0.21% ± 0.24%; range, 0.04% to 0.62%), whereas 22 (59%) showed a tremendous expansion of MDCs (9 patients: mean, 16.76% ± 14.03%; range, 1.36% to 41%), PDCs (4 patients: mean, 7.28% ± 6.84%; range, 1% to 14%), or both subsets (9 patients: MDC mean, 10.86% ± 12.36%; range, 1.02% to 37.1%; PDC mean, 4.25% ± 3.78%; range, 1.14% to 13.04%). Finally, in 4 patients (11%), no DC subsets were detectable. Both MDC and PDC subsets exhibited the original leukemic chromosomal abnormality. Ex vivo, leukemic PDCs, but not leukemic MDCs, had impaired capacity for maturation and decreased allostimulatory activity. Also, leukemic PDCs were altered in their ability to secrete interferon-α. These data provide evidence that DC subsets in vivo may be affected by leukemogenesis and may contribute to leukemia escape from immune control.

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Interleukin 10 Gene-Modified Bone Marrow-Derived Dendritic Cells Attenuate Liver Fibrosis in Mice by Inducing Regulatory T Cells and Inhibiting the TGF-β/Smad Signaling Pathway

Mediators of Inflammation ◽

10.1155/2019/4652596 ◽

2019 ◽

Vol 2019 ◽

pp. 1-15 ◽

Cited By ~ 5

Author(s):

Yejin Xu ◽

Xinyue Tang ◽

Min Yang ◽

Shengguo Zhang ◽

Shanshan Li ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Dendritic Cells ◽

Liver Fibrosis ◽

Regulatory T Cells ◽

Interleukin 10 ◽

Smad Signaling Pathway ◽

Culture Supernatants

Aim. To explore the therapeutic effects and mechanisms of interleukin 10 gene-modified bone marrow-derived dendritic cells (DC-IL10) on liver fibrosis. Methods. In vitro, BMDCs were transfected with lentiviral-interleukin 10-GFP (LV-IL10-GFP) at the MOI of 1 : 40. Then, the phenotype (MHCII, CD80, and CD86) and allo-stimulatory ability of DC-IL10 were identified by flow cytometry, and the levels of IL-10 and IL-12 (p70) secreted into the culture supernatants were quantified by ELISA. In vivo, DC-IL10 was injected into mice with CCl4-induced liver fibrosis through the tail vein. Lymphocytes were isolated to investigate the differentiation of T cells, and serum and liver tissue were collected for biochemical, cytokine, histopathologic, immune-histochemical, and Western blot analyzes. Results. In vitro, the expressions of MHCII, CD80, and CD86 in DC-IL10 were significantly suppressed, allogeneic CD4+T cells incubated with DC-IL10 showed a lower proliferative response, and the levels of IL-10 and IL-12 (p70) secreted into the DC-IL10 culture supernatants were significantly increased and decreased, respectively. In vivo, regulatory T cells (Tregs) were significantly increased, while ALT, AST, and inflammatory cytokines were significantly reduced in the DC-IL10 treatment group, and the degree of hepatic fibrosis was obviously reversed. The TGF-β/smad pathway was inhibited following DC-IL10 treatment compared to the liver fibrosis group. Conclusion. IL-10 genetic modification of BMDCs may maintain DC in the state of tolerance and allow DC to induce T cell hyporesponsiveness or tolerance. DC-IL10 suppressed liver fibrosis by inducing Treg production and inhibiting the TGF-β/smad signaling pathway.

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Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses

Blood ◽

10.1182/blood-2007-02-075945 ◽

2008 ◽

Vol 111 (12) ◽

pp. 5610-5620 ◽

Cited By ~ 209

Author(s):

Madeleine M. Hipp ◽

Norbert Hilf ◽

Steffen Walter ◽

Daniela Werth ◽

Katharina M. Brauer ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Immune Responses ◽

Map Kinases ◽

Kinase Inhibitors ◽

Mononuclear Cells ◽

Cytotoxic T Cell ◽

Peripheral Blood Mononuclear

AbstractThe tyrosine kinase inhibitors sorafenib and sunitinib are approved for the treatment of patients with malignant diseases. To analyze the possible use of these compounds in combination with immunotherapeutic approaches, we analyzed the effects of both inhibitors on the immunostimulatory capacity of human dendritic cells (DCs) and the induction of primary immune responses in vivo. Sorafenib, but not sunitinib, inhibits function of DCs, characterized by reduced secretion of cytokines and expression of CD1a, major histocompatibility complex, and costimulatory molecules in response to TLR ligands as well as by their impaired ability to migrate and stimulate T-cell responses. These inhibitory effects are mediated by inhibition of PI3 and MAP kinases and NFκB signaling. In contrast, sorafenib had no influence on the phenotype and proliferation of T cells. To analyze the effects of both TKIs on cytotoxic T-cell induction in vivo, C57BL/6 mice were pretreated with sorafenib or sunitinib and immunized with OVA257-264 peptide. Sorafenib, but not sunitinib, application significantly reduced the induction of antigen-specific T cells. Numbers of regulatory T cells were reduced in peripheral blood mononuclear cells from mice treated with sunitinib. These results indicate that sunitinib, but not sorafenib, is suitable for combination with immunotherapeutic approaches for treatment of cancer patients.

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