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 A subclass of dendritic cells kills CD4 T cells via Fas/Fas-ligand-induced apoptosis.

1996 ◽  
Vol 183 (4) ◽  
pp. 1789-1796 ◽  
Author(s):  
G Süss ◽  
K Shortman
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Fas Ligand ◽  
Activated T Cells ◽  
T Cell Apoptosis ◽  
Peripheral T Cells ◽  
Surface Staining ◽  
Induced Apoptosis ◽  
Antigen Presenting

Dendritic cells (DC), the most efficient antigen-presenting cells, are well equipped for activation of naive CD4+ T cells by their expression of high levels of major histocompatibility complex and costimulator molecules. We now demonstrate that some DC are equally well equipped for killing these same T cells. Murine splenic DC consist of both conventional CD8alpha- DC and a major population of CD8alpha+ DC. Whereas CD8- DC induce a vigorous proliferative response in CD4 T cells, CD8+ DC induce a lesser response that is associated with marked T cell apoptosis. By using various mixtures of T cells and DC from Fas-mutant lpr/lpr mice and Fas-ligand (FasL) mutant gld/gld mice, we show this death is due to interaction of Fas on activated T cells with FasL on CD8+ DC. Furthermore, we show by direct surface staining that CD8+ DC, but not CD8- DC, express FasL at high levels. These findings indicate that FasL+ CD8+ DC are a specialized subgroup of DC with a role in the regulation of the response of primary peripheral T cells.

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 Dendritic Cells: Cellular Mediators for Immunological Tolerance

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Chun Yuen J. Chung ◽  
Dirk Ysebaert ◽  
Zwi N. Berneman ◽  
Nathalie Cools
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Autoimmune Diseases ◽  
Inflammatory Diseases ◽  
Immunological Tolerance ◽  
Immunosuppressive Drugs ◽  
Peripheral Tolerance ◽  
Regulatory Function ◽  
Clonal Deletion

In general, immunological tolerance is acquired upon treatment with non-specific immunosuppressive drugs. This indiscriminate immunosuppression of the patient often causes serious side-effects, such as opportunistic infectious diseases. Therefore, the need for antigen-specific modulation of pathogenic immune responses is of crucial importance in the treatment of inflammatory diseases. In this perspective, dendritic cells (DCs) can have an important immune-regulatory function, besides their notorious antigen-presenting capacity. DCs appear to be essential for both central and peripheral tolerance. In the thymus, DCs are involved in clonal deletion of autoreactive immature T cells by presenting self-antigens. Additionally, tolerance is achieved by their interactions with T cells in the periphery and subsequent induction of T cell anergy, T cell deletion, and induction of regulatory T cells (Treg). Various studies have described, modulation of DC characteristics with the purpose to induce antigen-specific tolerance in autoimmune diseases, graft-versus-host-disease (GVHD), and transplantations. Promising results in animal models have prompted researchers to initiate first-in-men clinical trials. The purpose of current review is to provide an overview of the role of DCs in the immunopathogenesis of autoimmunity, as well as recent concepts of dendritic cell-based therapeutic opportunities in autoimmune diseases.

scholarly journals Dendritic cells and isolevuglandins in immunity, inflammation, and hypertension

2017 ◽  
Vol 312 (3) ◽  
pp. H368-H374 ◽  
Author(s):  
Kala B. Dixon ◽  
Sean S. Davies ◽  
Annet Kirabo
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Protein Modification ◽  
Vascular Dysfunction ◽  
Organ Damage ◽  
Activated T Cells ◽  
Adaptive Immune ◽  
The Past ◽  
Antigen Presenting

Hypertension is the major risk factor for morbidity and mortality from myocardial infarction, stroke, heart failure, and chronic kidney disease. Despite its importance, the pathogenesis of essential hypertension is poorly understood. During the past several years, it has become evident that T cells contribute to hypertension. Activated T cells accumulate in the perivascular space and the kidney and release cytokines that promote vascular dysfunction and end-organ damage. Although dendritic cells play a pivotal role in initiating adaptive immune responses, T cells have taken center stage in studies implicating the immune system in the genesis of hypertension. The mechanisms by which T cells are activated and the antigens involved are poorly understood. We recently showed that hypertension is associated with increased dendritic cell production of the TH17 polarizing cytokines, IL-6, IL-1β, and IL-23. This occurs in part by increased superoxide production via NADPH oxidase and protein modification by highly reactive isolevuglandins (IsoLGs). IsoLGs are produced via the isoprostane pathway of free radical-mediated lipid peroxidation and, when adducted to proteins, have the potential to act as neoantigens. In this review, we discuss recent advances in our understanding of the role of antigen-presenting dendritic cells in the pathophysiology of hypertension and highlight potential neoantigens that may contribute to this disease.

scholarly journals The antigen-presenting activities of Ia+ dendritic cells shift dynamically from lung to lymph node after an airway challenge with soluble antigen.

1995 ◽  
Vol 181 (4) ◽  
pp. 1275-1283 ◽  
Author(s):  
W Xia ◽  
C E Pinto ◽  
R L Kradin
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Lymph Node ◽  
Mononuclear Cells ◽  
Antigen Expression ◽  
Soluble Antigen ◽  
Regional Lymph Nodes ◽  
Antigen Presenting

Dendritic cells (DC) are widely distributed in the lung where they are distinguished by their morphology and class II major histocompatibility complex (Ia) antigen expression. Although a role for DC as pulmonary antigen-presenting cell (APC) has been suggested, little is currently known concerning how these cells respond to inhaled antigens in vivo. Hen-egg lysozyme (HEL) was injected intratracheally into Lewis rats; DC were subsequently purified from the lung and regional lymph nodes (LN) at intervals of up to 14 d and examined for their ability to stimulate the proliferation of HEL-immune T cells in vitro in the absence of added HEL. Pulmonary DC displayed APC activities at 3 h and for up to 7 d after the injection of antigen. Dendritic cells in the draining hilar LN showed APC activities that appeared at 24 h, peaked at day 3, and then diminished progressively. After the primary sensitization, HEL-immune T cells were detected in hilar LN but not in the lung. A second airway challenge with HEL at day 14 yielded an antigen-specific pulmonary immune response, characterized histologically by the accumulation of mononuclear cells around lung venules. We conclude that APC activities shift from lung to lymph node during the response to inhaled antigen.

Detection of self-reactive CD8+T cells with an anergic phenotype in healthy individuals

Science ◽  
2014 ◽  
Vol 346 (6216) ◽  
pp. 1536-1540 ◽  
Author(s):  
Yuka Maeda ◽  
Hiroyoshi Nishikawa ◽  
Daisuke Sugiyama ◽  
Danbee Ha ◽  
Masahide Hamaguchi ◽  
...  
Keyword(s):  
T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
Immunological Tolerance ◽  
Healthy Individuals ◽  
Activated T Cells ◽  
Cognate Antigen ◽  
Anergic T Cells ◽  
Antigen Presenting

Immunological tolerance to self requires naturally occurring regulatory T (Treg) cells. Yet how they stably control autoimmune T cells remains obscure. Here, we show that Tregcells can render self-reactive human CD8+T cells anergic (i.e., hypoproliferative and cytokine hypoproducing upon antigen restimulation) in vitro, likely by controlling the costimulatory function of antigen-presenting cells. Anergic T cells were naïve in phenotype, lower than activated T cells in T cell receptor affinity for cognate antigen, and expressed several coinhibitory molecules, including cytotoxic T lymphocyte–associated antigen-4 (CTLA-4). Using these criteria, we detected in healthy individuals anergic T cells reactive with a skin antigen targeted in the autoimmune disease vitiligo. Collectively, our results suggest that Tregcell–mediated induction of anergy in autoimmune T cells is important for maintaining self-tolerance.

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.

Sign in / Sign up

Export Citation Format

Share Document