scholarly journals Foxp3+ CD4+ regulatory T cells control dendritic cells in inducing antigen-specific immunity to emerging SARS-CoV-2 antigens

2021 ◽  
Vol 17 (12) ◽  
pp. e1010085
Author(s):  
Ryuta Uraki ◽  
Masaki Imai ◽  
Mutsumi Ito ◽  
Hiroaki Shime ◽  
Mizuyu Odanaka ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Treg Cell ◽  
Treg Cells ◽  
Immunological Tolerance ◽  
Cell Depletion ◽  
Humoral And Cellular Immunity ◽  
Specific Immunity ◽  
Antigen Presenting

Regulatory T (Treg) cells, which constitute about 5–10% of CD4+T cells expressing Foxp3 transcription factor and CD25(IL-2 receptor α chain), are key regulators in controlling immunological self-tolerance and various immune responses. However, how Treg cells control antigen-specific immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. In this study, we examined the effect of transient breakdown of the immunological tolerance induced by Treg-cell depletion on adaptive immune responses against administered SARS-CoV-2 antigen, spike protein 1 (S1). Notably, without the use of adjuvants, transient Treg-cell depletion in mice induced anti-S1 antibodies that neutralized authentic SARS-CoV-2, follicular helper T cell formation and S1-binding germinal center B cell responses, but prevented the onset of developing autoimmune diseases. To further clarify the mechanisms, we investigated maturation of dendritic cells (DCs), which is essential to initiate antigen-specific immunity. We found that the transient Treg-cell depletion resulted in maturation of both migratory and resident DCs in draining lymph nodes that captured S1-antigen. Moreover, we observed S1-specific CD4+ T cells and CD8+ T cells with interferon-γ production. Thus, captured S1 was successfully presented by DCs, including cross-presentation to CD8+ T cells. These data indicate that transient Treg-cell depletion in the absence of adjuvants induces maturation of antigen-presenting DCs and succeeds in generating antigen-specific humoral and cellular immunity against emerging SARS-CoV-2 antigens. Finally, we showed that SARS-CoV-2 antigen-specific immune responses induced by transient Treg-cell depletion in the absence of adjuvants were compatible with those induced with an effective adjuvant, polyriboinosinic:polyribocytidyl acid (poly IC) and that the combination of transient Treg-cell depletion with poly IC induced potent responses. These findings highlight the capacity for manipulating Treg cells to induce protective adaptive immunity to SARS-CoV-2 with activating antigen-presenting DCs, which may improve the efficacy of ongoing vaccine therapies and help enhance responses to emerging SARS-CoV-2 variants.

scholarly journals Evaluation of Feline Monocyte-Derived Dendritic Cells Loaded with Internally Inactivated Virus as a Vaccine against Feline Immunodeficiency Virus

2008 ◽  
Vol 15 (3) ◽  
pp. 452-459 ◽  
Author(s):  
Giulia Freer ◽  
Donatella Matteucci ◽  
Paola Mazzetti ◽  
Francesca Tarabella ◽  
Valentina Catalucci ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Immune Functions ◽  
Peripheral Blood Mononuclear ◽  
Challenge Virus ◽  
Homologous Virus ◽  
Antibody Titers ◽  
Cellular Immune ◽  
Antigen Presenting

ABSTRACT Dendritic cells are the only antigen-presenting cells that can present exogenous antigens to both helper and cytolytic T cells and prime Th1-type or Th2-type cellular immune responses. Given their unique immune functions, dendritic cells are considered attractive “live adjuvants” for vaccination and immunotherapy against cancer and infectious diseases. The present study was carried out to assess whether the reinjection of autologous monocyte-derived dendritic cells loaded with an aldithriol-2-inactivated primary isolate of feline immune deficiency virus (FIV) was able to elicit protective immune responses against the homologous virus in naive cats. Vaccine efficacy was assessed by monitoring immune responses and, finally, by challenge with the homologous virus of vaccinated, mock-vaccinated, and healthy cats. The outcome of challenge was followed by measuring cellular and antibody responses and viral and proviral loads and quantitating FIV by isolation and a count of CD4+/CD8+ T cells in blood. Vaccinated animals exhibited clearly evident FIV-specific peripheral blood mononuclear cell proliferation and antibody titers in response to immunization; however, they became infected with the challenge virus at rates comparable to those of control animals.

scholarly journals Antigen-specific Treg cells in immunological tolerance: implications for allergic diseases

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 38 ◽  
Author(s):  
Azza Abdel-Gadir ◽  
Amir H. Massoud ◽  
Talal A. Chatila
Keyword(s):  
Immune Responses ◽  
Treg Cell ◽  
Allergic Diseases ◽  
Treg Cells ◽  
Immunological Tolerance ◽  
Inflammatory Disorders ◽  
Cell Responses ◽  
Recent Advances ◽  
And Function ◽  
Is Failure

Allergic diseases are chronic inflammatory disorders in which there is failure to mount effective tolerogenic immune responses to inciting allergens. The alarming rise in the prevalence of allergic diseases in recent decades has spurred investigations to elucidate the mechanisms of breakdown in tolerance in these disorders and means of restoring it. Tolerance to allergens is critically dependent on the generation of allergen-specific regulatory T (Treg) cells, which mediate a state of sustained non-responsiveness to the offending allergen. In this review, we summarize recent advances in our understanding of mechanisms governing the generation and function of allergen-specific Treg cells and their subversion in allergic diseases. We will also outline approaches to harness allergen-specific Treg cell responses to restore tolerance in these disorders.

scholarly journals TIGIT-Fc as a Potential Therapeutic Agent for Fetomaternal Tolerance

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenyan Fu ◽  
Renfei Cai ◽  
Zetong Ma ◽  
Tian Li ◽  
Changhai Lei ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Interleukin 10 ◽  
Immunological Tolerance ◽  
Tolerogenic Dendritic Cells ◽  
Immune Cell Subsets ◽  
Pregnant Mice ◽  
Antigen Presenting

The perfect synchronization of maternal immune-endocrine mechanisms and those of the fetus is necessary for a successful pregnancy. In this report, decidual immune cells at the maternal-fetal interface were detected that expressed TIGIT (T cell immunoreceptor with Ig and ITIM domains), which is a co-inhibitory receptor that triggers immunological tolerance. We generated recombinant TIGIT-Fc fusion proteins by linking the extracellular domain of TIGIT and silent Fc fragments. The treatment with TIGIT-Fc of human decidual antigen presenting cells (APCs), the decidual dendritic cells (dDCs), and decidual macrophages (dMϕs) increased the production of interleukin 10 and induced the decidua APCs to powerfully polarize the decidual CD4+ T cells toward a classic TH2 phenotype. We further proposed that Notch signaling shows a pivotal effect on the transcriptional regulation in decidual immune cell subsets. Moreover, the administration of TIGIT-Fc to CBA/J pregnant mice at preimplantation induced CD4+ forkhead box P3+ (Foxp3+) regulatory T cells and tolerogenic dendritic cells and increased pregnancy rates in an abortion-prone animal model stress. The results suggested the therapeutic potential of the TIGIT-Fc fusion protein in reinstating immune tolerance in failing pregnancies.

scholarly journals Interleukin-12p70 Expression by Dendritic Cells of HIV-1-Infected Patients Fails to Stimulategag-Specific Immune Responses

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Ellen Van Gulck ◽  
Nathalie Cools ◽  
Derek Atkinson ◽  
Lotte Bracke ◽  
Katleen Vereecken ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Hiv Replication ◽  
Cell Responses ◽  
Antigen Presenting ◽  
Hiv 1 ◽  
Unique Capability

A variety of immune-based therapies has been developed in order to boost or induce protective CD8+T cell responses in order to control HIV replication. Since dendritic cells (DCs) are professional antigen-presenting cells (APCs) with the unique capability to stimulate naïve T cells into effector T cells, their use for the induction of HIV-specific immune responses has been studied intensively. In the present study we investigated whether modulation of the activation state of DCs electroporated with consensus codon-optimized HxB2gagmRNA enhances their capacity to induce HIVgag-specific T cell responses. To this end, mature DCs were (i) co-electroporated with mRNA encoding interleukin (IL)-12p70 mRNA, or (ii) activated with a cytokine cocktail consisting of R848 and interferon (IFN)-γ. Our results confirm the ability of HxB2gag-expressing DCs to expand functional HIV-specific CD8+T cells. However, although most of the patients had detectablegag-specific CD8+T cell responses, no significant differences in the level of expansion of functional CD8+T cells could be demonstrated when comparing conventional or immune-modulated DCs expressing IL-12p70. This result which goes against expectation may lead to a re-evaluation of the need for IL-12 expression by DCs in order to improve T-cell responses in HIV-1-infected individuals.

A Dendritic Cells-Targeting Nano-Vaccine by Coupling Polylactic-Co-Glycolic Acid-Encapsulated Allergen with Mannan Induces Regulatory T Cells

2021 ◽  
pp. 1-11
Author(s):  
He Wen ◽  
Litian Qu ◽  
Yu Zhang ◽  
Beilei Xu ◽  
Shiqi Ling ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Glycolic Acid ◽  
Tolerance Induction ◽  
Treg Cells ◽  
Intercellular Adhesion Molecule ◽  
Allergen Specific Immunotherapy ◽  
Th2 Immune Response

<b><i>Background:</i></b> The efficacy of allergen-specific immunotherapy (AIT) is mainly depended on the tolerogenic immune responses elicited. Properly conjugated nano-vaccine has the advantages of both specific targeting and continuous and on-demand release of allergen. <b><i>Objectives:</i></b> The aim of this study is to investigate the effects of a dendritic cells (DCs)-targeting nano-vaccine for AIT. <b><i>Methods:</i></b> The nano-vaccine was produced by coupling polylactic-co-glycolic acid (PLGA)-encapsulated ovalbumin (OVA) with mannan. Allergen capture, human monocytes-derived DCs (hMoDCs) activation, and T cells responses were assessed by flow cytometry, confocal microscopy, quantitative real-time PCR, ELISA, and Cytometric Bead Array. Balb/c mice were immunized with the nano-vaccines, and the immune responses were analyzed. <b><i>Results:</i></b> OVA-PLGA nanoparticle (NP) displayed favorable safety profile. OVA-mannan-PLGA NP was captured more efficiently by hMoDCs than OVA-PLGA NP, which was mediated mainly through DC-specific intercellular adhesion molecule 3-grabbing nonintegrin. A tolerogenic phenotype of hMoDCs was induced by OVA-mannan-PLGA NP, but not OVA-PLGA NP, and increased number of regulatory T (Treg) cells was generated subsequently in in vitro coculture. Immunization of Balb/c mice with OVA-mannan-PLGA NP resulted in lower serum level of OVA-specific immunoglobulins and less production of pro-inflammatory cytokines in splenocytes culture than the mice immunized with OVA-PLAG NP, PLGA NP, or OVA, while the number of splenic Treg cells was higher in OVA-mannan-PLGA group than in other groups. Moreover, preimmunization with OVA-mannan-PLGA NP significantly inhibited the Th2 immune response induced by OVA sensitization. <b><i>Conclusions:</i></b> The biocompatible PLGA-encapsulated OVA coupling with mannan has augmented ability for tolerance induction and could be developed as a novel vaccine for AIT.

scholarly journals Lymph Node-Targeted Synthetically Glycosylated Antigen Leads to Antigen-Specific Immunological Tolerance

2021 ◽  
Vol 12 ◽  
Author(s):  
Chitavi D. Maulloo ◽  
Shijie Cao ◽  
Elyse A. Watkins ◽  
Michal M. Raczy ◽  
Ani. S. Solanki ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Lymph Node ◽  
Subcutaneous Administration ◽  
Immunological Tolerance ◽  
T Cell Tolerance ◽  
Clonal Deletion ◽  
Activated T Cells ◽  
Cellular Target ◽  
Antigen Presenting

Inverse vaccines that tolerogenically target antigens to antigen-presenting cells (APCs) offer promise in prevention of immunity to allergens and protein drugs and treatment of autoimmunity. We have previously shown that targeting hepatic APCs through intravenous injection of synthetically glycosylated antigen leads to effective induction of antigen-specific immunological tolerance. Here, we demonstrate that targeting these glycoconjugates to lymph node (LN) APCs under homeostatic conditions leads to local and increased accumulation in the LNs compared to unmodified antigen and induces a tolerogenic state both locally and systemically. Subcutaneous administration directs the polymeric glycoconjugate to the draining LN, where the glycoconjugated antigen generates robust antigen-specific CD4+ and CD8+ T cell tolerance and hypo-responsiveness to antigenic challenge via a number of mechanisms, including clonal deletion, anergy of activated T cells, and expansion of regulatory T cells. Lag-3 up-regulation on CD4+ and CD8+ T cells represents an essential mechanism of suppression. Additionally, presentation of antigen released from the glycoconjugate to naïve T cells is mediated mainly by LN-resident CD8+ and CD11b+ dendritic cells. Thus, here we demonstrate that antigen targeting via synthetic glycosylation to impart affinity for APC scavenger receptors generates tolerance when LN dendritic cells are the cellular target.

scholarly journals Humoral immune response to adenovirus induce tolerogenic bystander dendritic cells that promote generation of regulatory T cells

2018 ◽  
Author(s):  
Thi Thu Phuong Tran ◽  
Karsten Eichholz ◽  
Patrizia Amelio ◽  
Crystal Moyer ◽  
Glen R Nemerow ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Persistent Infections ◽  
Cell Immunity ◽  
Tolerogenic Dendritic Cells ◽  
Antigen Presenting ◽  
Tolerogenic Dcs

AbstractFollowing repeated encounters with adenoviruses most of us develop robust humoral and cellular immune responses that are thought to act together to combat ongoing and subsequent infections. Yet in spite of robust immune responses, adenoviruses establish subclinical persistent infections that can last for decades. While adenovirus persistence pose minimal risk in B-cell compromised individuals, if T-cell immunity is severely compromised, reactivation of latent adenoviruses can be life threatening. This dichotomy led us to ask how anti-adenovirus antibodies influence adenovirus-specific T-cell immunity. Using primary human blood cells, transcriptome and secretome profiling, and pharmacological, biochemical, genetic, molecular, and cell biological approaches, we initially found that healthy adults harbor adenovirus-specific regulatory T cells (Tregs). As peripherally induced Tregsare generated by tolerogenic dendritic cells (DCs), we then addressed how tolerogenic DCs could be created. Here, we demonstrate that DCs that take up immunoglobulin-complexed (IC)-adenoviruses create an environment that causes bystander DCs to become tolerogenic. These adenovirus antigen-loaded tolerogenic DCs can drive naïve T cells to mature into adenovirus-specific Tregs. Our results may provide ways to improve antiviral therapy and/or pre-screening high-risk individuals undergoing immunosuppression.Author summaryWhile numerous studies have addressed the cellular and humoral response to primary virus encounters, relatively little is known about the interplay between persistent infections, neutralizing antibodies, antigen-presenting cells, and the T-cell response. Our studies suggests that if adenovirus–antibody complexes are taken up by professional antigen-presenting cells (dendritic cells), the DCs generate an environment that causes bystander dendritic cells to become tolerogenic. These tolerogenic dendritic cells favors the creation of adenovirus-specific regulatory T cells. While this pathway likely favors pathogen survival, there may be advantages for the host also.

scholarly journals Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines

Blood ◽  
2008 ◽  
Vol 112 (3) ◽  
pp. 610-618 ◽  
Author(s):  
Michael A. Morse ◽  
Amy C. Hobeika ◽  
Takuya Osada ◽  
Delila Serra ◽  
Donna Niedzwiecki ◽  
...  
Keyword(s):  
Single Dose ◽  
T Cell ◽  
Immune Responses ◽  
Treg Cell ◽  
Dose Group ◽  
Flow Cytometric Analysis ◽  
Treg Cells ◽  
T Cell Response ◽  
Cell Depletion ◽  
Denileukin Diftitox

Abstract CD4+CD25highFoxP3+ regulatory T (Treg) cells limit antigen-specific immune responses and are a cause of suppressed anticancer immunity. In preclinical and clinical studies, we assessed the immune consequences of FoxP3+ Treg-cell depletion in patients with advanced malignancies. We demonstrated that a CD25high targeting immunotoxin (denileukin diftitox) depleted FoxP3+ Treg cells, decreased Treg-cell function, and enhanced antigen-specific T-cell responses in vitro. We then attempted to enhance antitumor immune responses in patients with carcinoembryonic antigen (CEA)–expressing malignancies by Treg-cell depletion. In a pilot study (n = 15), denileukin diftitox, given as a single dose or repeated dosing, was followed by immunizations with dendritic cells modified with the fowlpox vector rF-CEA(6D)-TRICOM. By flow cytometric analysis, we report the first direct evidence that circulating CD4+CD25highFoxP3+ Treg cells are depleted after multiple doses of denileukin diftitox. Earlier induction of, and overall greater exposure to, the T-cell response to CEA was observed in the multiple-dose group, but not the single-dose group. These results indicate the potential for combining Treg-cell depletion with anticancer vaccines to enhance tumor antigen-specific immune responses and the need to explore dose and schedule of Treg depletion strategies in optimiz-ing vaccine efforts. This trial was registered at www.clinicaltrials.gov as no. NCT00128622.

scholarly journals Regulation of Murine Dendritic Cell Immune Responses by Helicobacter felis Antigen

2006 ◽  
Vol 74 (8) ◽  
pp. 4624-4633 ◽  
Author(s):  
Maureen L. Drakes ◽  
Steven J. Czinn ◽  
Thomas G. Blanchard
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Immune Responses ◽  
Lamina Propria ◽  
Adaptive Immune Responses ◽  
Helicobacter Felis ◽  
Adaptive Immune ◽  
Pulsed Dc ◽  
Antigen Presenting

ABSTRACT Helicobacter infections are present in approximately 50% of humans, causing severe illnesses such as gastritis and malignancies. Dendritic cells (DC) are critical antigen-presenting cells which link innate and adaptive immune responses. The mechanism of dendritic cell regulation in Helicobacter-induced gastritis is poorly understood. These studies characterized DC isolated from the lamina propria of Helicobacter-infected mice and analyzed innate and adaptive immune responses elicited by Helicobacter antigen (Ag)-pulsed DC. The presence of DC was elevated in the gastric lamina propria infiltrate of infected mice in comparison with controls. After treatment with Helicobacter felis Ag, DC were polarized to secrete interleukin-6 as the dominant cytokine. In the presence of DC and Helicobacter Ag, responder allogeneic T cells in culture exhibited limited cell division. We suggest that the response of DC and T cells to Helicobacter Ag is critical to the chronic persistence of Helicobacter-induced gastritis.

scholarly journals TRAF3 regulates the effector function of regulatory T cells and humoral immune responses

2013 ◽  
Vol 211 (1) ◽  
pp. 137-151 ◽  
Author(s):  
Jae-Hoon Chang ◽  
Hongbo Hu ◽  
Jin Jin ◽  
Nahum Puebla-Osorio ◽  
Yichuan Xiao ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Treg Cell ◽  
Cell Function ◽  
Treg Cells ◽  
Antibody Responses ◽  
Effector Memory ◽  
Humoral Immune ◽  
Treg Cell Function

Regulatory T cells (Treg cells) control different aspects of immune responses, but how the effector functions of Treg cells are regulated is incompletely understood. Here we identified TNF receptor–associated factor 3 (TRAF3) as a regulator of Treg cell function. Treg cell–specific ablation of TRAF3 impaired CD4 T cell homeostasis, characterized by an increase in the Th1 type of effector/memory T cells. Moreover, the ablation of TRAF3 in Treg cells resulted in increased antigen-stimulated activation of follicular T helper cells (TFH cells), coupled with heightened formation of germinal centers and production of high-affinity IgG antibodies. Although the loss of TRAF3 did not reduce the overall frequency of Treg cells, it attenuated the antigen-stimulated production of follicular Treg cells (TFR cells). TRAF3 signaling in Treg cells was required to maintain high level expression of inducible co-stimulator (ICOS), which in turn was required for TFR cell generation and inhibition of antibody responses. These findings establish TRAF3 as a mediator of Treg cell function in the regulation of antibody responses and suggest a role for TRAF3 in mediating ICOS expression in Treg cells.

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