TIGIT-Fc as a Potential Therapeutic Agent for Fetomaternal Tolerance

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.

Download Full-text

TIGIT-Fc Promote Immune Tolerance at the Feto-maternal Interface

10.1101/819243 ◽

2019 ◽

Cited By ~ 2

Author(s):

Wenyan Fu ◽

Zetong Ma ◽

Changhai Lei ◽

Min Ding ◽

Shi Hu

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Immune Tolerance ◽

Immune Cell ◽

Therapeutic Potential ◽

Interleukin 10 ◽

Immunological Tolerance ◽

Direct Role ◽

Tolerogenic Dendritic Cells ◽

Pregnant Mice

AbstractThe perfect synchronization of maternal immune-endocrine mechanisms and those of the foetus is necessary for a successful pregnancy. In this report, decidual immune cells at the maternal-foetal 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 dendritic cells (dDCs) increased the production of interleukin 10 and induced the dDCs to powerfully polarize the decidual CD4+ T cells towards a classic TH2 phenotype. 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 a mouse model of abortive stress. Moreover, we proposed that progesterone play a direct role in the transcriptional regulation of the TIGIT gene in decidual immune cell subsets. The results suggested the therapeutic potential of the TIGIT-Fc fusion protein in reinstating immune tolerance in failing pregnancies.

Download Full-text

Immunomodulatory Role and Therapeutic Potential of Non-Coding RNAs Mediated by Dendritic Cells in Autoimmune and Immune Tolerance-Related Diseases

Frontiers in Immunology ◽

10.3389/fimmu.2021.678918 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yifeng Liu ◽

Xiaoze Wang ◽

Fan Yang ◽

Yanyi Zheng ◽

Tinghong Ye ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Autoimmune Diseases ◽

Immune Tolerance ◽

Therapeutic Potential ◽

The Body ◽

Cytokines And Chemokines ◽

Non Coding Rnas ◽

And Function ◽

Antigen Presenting

Dendritic cells (DCs) are professional antigen-presenting cells that act as a bridge between innate immunity and adaptive immunity. After activation, DCs differentiate into subtypes with different functions, at which point they upregulate co-stimulatory molecules and produce various cytokines and chemokines. Activated DCs also process antigens for presentation to T cells and regulate the differentiation and function of T cells to modulate the immune state of the body. Non-coding RNAs, RNA transcripts that are unable to encode proteins, not only participate in the pathological mechanisms of autoimmune-related diseases but also regulate the function of immune cells in these diseases. Accumulating evidence suggests that dysregulation of non-coding RNAs contributes to DC differentiation, functions, and so on, consequently producing effects in various autoimmune diseases. In this review, we summarize the main non-coding RNAs (miRNAs, lncRNAs, circRNAs) that regulate DCs in pathological mechanisms and have tremendous potential to give rise to novel therapeutic targets and strategies for multiple autoimmune diseases and immune tolerance-related diseases.

Download Full-text

Vitamin D3-Induced Tolerogenic Dendritic Cells Modulate the Transcriptomic Profile of T CD4+ Cells Towards a Functional Hyporesponsiveness

Frontiers in Immunology ◽

10.3389/fimmu.2020.599623 ◽

2021 ◽

Vol 11 ◽

Author(s):

Juan Navarro-Barriuso ◽

María José Mansilla ◽

Bibiana Quirant-Sánchez ◽

Aina Teniente-Serra ◽

Cristina Ramo-Tello ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Vitamin D3 ◽

Therapeutic Potential ◽

Promising Alternative ◽

Transcriptomic Profile ◽

Tolerogenic Dendritic Cells ◽

Potential Biomarker ◽

Relative Prevalence ◽

Regulatory Properties

The use of autologous tolerogenic dendritic cells (tolDC) has become a promising alternative for the treatment of autoimmune diseases. Among the different strategies available, the use of vitamin D3 for the generation of tolDC (vitD3-tolDC) constitutes one of the most robust approaches due to their immune regulatory properties, which are currently being tested in clinical trials. However, the mechanisms that vitD3-tolDC trigger for the induction of tolerance remain elusive. For this reason, we performed a full phenotypical, functional, and transcriptomic characterization of T cells upon their interaction with autologous, antigen-specific vitD3-tolDC. We observed a strong antigen-specific reduction of T cell proliferation, combined with a decrease in the relative prevalence of TH1 subpopulations and IFN-γ production. The analysis of the transcriptomic profile of T CD4+ cells evidenced a significant down-modulation of genes involved in cell cycle and cell response to mainly pro-inflammatory immune-related stimuli, highlighting the role of JUNB gene as a potential biomarker of these processes. Consequently, our results show the induction of a strong antigen-specific hyporesponsiveness combined with a reduction on the TH1 immune profile of T cells upon their interaction with vitD3-tolDC, which manifests the regulatory properties of these cells and, therefore, their therapeutic potential in the clinic.

Download Full-text

Overexpression of miR-223 Promotes Tolerogenic Properties of Dendritic Cells Involved in Heart Transplantation Tolerance by Targeting Irak1

Frontiers in Immunology ◽

10.3389/fimmu.2021.676337 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shun Yuan ◽

Yuanyang Chen ◽

Min Zhang ◽

Zhiwei Wang ◽

Zhipeng Hu ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Heart Transplantation ◽

Immune Cell ◽

Transplant Rejection ◽

Control Group ◽

Rna Molecules ◽

Heart Graft ◽

Non Coding Rna ◽

Antigen Presenting

Dendritic cells (DCs) are key mediators of transplant rejection. Numerous factors have been identified that regulate transplant immunopathology by modulating the function of DCs. Among these, microRNAs (miRNAs), small non-coding RNA molecules, have received much attention. The miRNA miR-223 is very highly expressed and tightly regulated in hematopoietic cells. It plays an important role in modulating the immune response by regulating neutrophils and macrophages, and its dysregulation contributes to multiple types of immune diseases. However, the role of miR-223 in immune rejection is unclear. Here, we observed expression of miR-223 in patients and mice who had undergone heart transplantation and found that it increased in the serum of both, and also in DCs from the spleens of recipient mice, although it was unchanged in splenic T cells. We also found that miR-223 expression decreased in lipopolysaccharide-stimulated DCs. Increasing the level of miR-223 in DCs promoted polarization of DCs toward a tolerogenic phenotype, which indicates that miR-223 can attenuate activation and maturation of DCs. MiR-223 effectively induced regulatory T cells (Tregs) by inhibiting the function of antigen-presenting DCs. In addition, we identified Irak1 as a miR-223 target gene and an essential regulator of DC maturation. In mouse allogeneic heterotopic heart transplantation models, grafts survived longer and suffered less immune cell infiltration in mice with miR-223-overexpressing immature (im)DCs. In the miR-223-overexpressing imDC recipients, T cells from spleen differentiated into Tregs, and the level of IL-10 in heart grafts was markedly higher than that in the control group. In conclusion, miR-223 regulates the function of DCs via Irak1, differentiation of T cells into Tregs, and secretion of IL-10, thereby suppressing allogeneic heart graft rejection.

Download Full-text

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

Frontiers in Immunology ◽

10.3389/fimmu.2021.714842 ◽

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.

Download Full-text

Differences in Host Immune Populations Between Rhesus Macaques and Cynomolgus Macaque Subspecies, in Relation to Susceptibility to Mycobacterium Tuberculosis Infection.

10.21203/rs.3.rs-252046/v1 ◽

2021 ◽

Author(s):

Laura Sibley ◽

Owen Daykin-Pont ◽

Charlotte Sarfas ◽

Jordan Pascoe ◽

Alexandra Morrison ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Mycobacterium Tuberculosis ◽

Immune Cell ◽

Rhesus Macaques ◽

Cynomolgus Macaque ◽

Myeloid Dendritic Cells ◽

Mycobacterium Tuberculosis Infection ◽

Macaque Species ◽

Immune Cell Subsets

Abstract Rhesus (Macaca mulatta) and cynomolgus (Macaca fasicularis) macaques of distinct genetic origin are understood to vary in susceptibility to Mycobacterium tuberculosis, and therefore differences in their immune systems may account for the differences in disease control. Monocyte:lymphocyte (M:L) ratio has been identified as a risk factor for M. tuberculosis infection and is known to vary between macaque species. We aimed to characterise the constituent monocyte and lymphocyte populations between macaque species, and profile other major immune cell subsets including: CD4+ and CD8+ T-cells, NK-cells, B-cells, monocyte subsets and myeloid dendritic cells. We found immune cell subsets to vary significantly between macaque species. Frequencies of CD4+ and CD8+ T-cells and the CD4:CD8 ratio showed significant separation between species, while myeloid dendritic cells best associated macaque populations by M. tuberculosis susceptibility. A more comprehensive understanding of the immune parameters between macaque species may contribute to the identification of new biomarkers and correlates of protection.

Download Full-text

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

10.1101/334508 ◽

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.

Download Full-text

Heavy chain ferritin activates regulatory T cells by induction of changes in dendritic cells

Blood ◽

10.1182/blood.v99.9.3326 ◽

2002 ◽

Vol 99 (9) ◽

pp. 3326-3334 ◽

Cited By ~ 71

Author(s):

Christian P. Gray ◽

Paolo Arosio ◽

Peter Hersey

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Monoclonal Antibodies ◽

Regulatory T Cells ◽

Heavy Chain ◽

Death Receptor ◽

Interleukin 10 ◽

Interferon Γ ◽

Direct Production ◽

Antigen Presenting

Abstract Heavy chain ferritin (H-ferritin) is a component of the iron-binding protein, ferritin. We have previously shown that H-ferritin inhibits anti-CD3–stimulated lymphocyte proliferation and that this was due to increased production of interleukin-10 (IL-10). In the present study we have shown that induction of IL-10 production was due to effects of H-ferritin on adherent antigen-presenting cells (APCs) in blood and monocyte-derived dendritic cells (MoDCs). IL-10 was produced by a subpopulation of CD4 T cells, which expressed the CD25 component of the IL-2 receptor and the CTLA-4 receptor characteristic of regulatory T cells. The changes induced in MoDCs were compared with those induced by CD40L and their significance tested by inhibition with monoclonal antibodies. These studies indicated that H-ferritin induced relatively greater expression of CD86 and B7-H1 on MoDCs and that monoclonal antibodies against their receptors, CTLA-4 and programmed death receptor-1 (PD-1), inhibited IL-10 production from the regulatory T cells. H-ferritin did not appear to induce direct production of the cytokines IL-2, IL-4, IL-6, IL-10, IL-12, or interferon-γ from the DCs. These results are consistent with the thesis that H-ferritin induces B7-H1 and CD86 (B7-2) on APCs, which in turn induce IL-10 production from regulatory T cells. This is possibly one mechanism by which melanoma cells may induce changes in APCs in the vicinity of the tumor and result in suppression of immune responses by induction of regulatory T cells.

Download Full-text

Retroviral and Lentiviral Vectors for the Induction of Immunological Tolerance

Scientifica ◽

10.6064/2012/694137 ◽

2012 ◽

Vol 2012 ◽

pp. 1-14 ◽

Cited By ~ 12

Author(s):

Inès Dufait ◽

Therese Liechtenstein ◽

Alessio Lanna ◽

Christopher Bricogne ◽

Roberta Laranga ◽

...

Keyword(s):

Dendritic Cells ◽

Lentiviral Vector ◽

Lentiviral Vectors ◽

Immunological Tolerance ◽

Target Cells ◽

Intracellular Signalling Pathways ◽

Tolerogenic Dendritic Cells ◽

Antigen Presenting ◽

Immunosuppressive Cytokines

Retroviral and lentiviral vectors have proven to be particularly efficient systems to deliver genes of interest into target cells, either in vivo or in cell cultures. They have been used for some time for gene therapy and the development of gene vaccines. Recently retroviral and lentiviral vectors have been used to generate tolerogenic dendritic cells, key professional antigen presenting cells that regulate immune responses. Thus, three main approaches have been undertaken to induce immunological tolerance; delivery of potent immunosuppressive cytokines and other molecules, modification of intracellular signalling pathways in dendritic cells, and de-targeting transgene expression from dendritic cells using microRNA technology. In this review we briefly describe retroviral and lentiviral vector biology, and their application to induce immunological tolerance.

Download Full-text

IMMU-46. ARTIFICIAL INTELLIGENCE-DIRECTED, GENE THERAPY-BASED TRANSDIFFERENTIATION OF GLIOBLASTOMA TO FUNCTIONAL DENDRITIC CELLS AS NOVEL CANCER IMMUNOTHERAPY

Neuro-Oncology ◽

10.1093/neuonc/noab196.405 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi103-vi103

Author(s):

Dan Jin ◽

Son Le ◽

Mathew Sebastian ◽

Dongjiang Chen ◽

Linchun Jin ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cell Fate ◽

Antigen Processing ◽

Immune Cell ◽

Viral Vector ◽

T Cell Response ◽

Cell Trafficking ◽

Novel Approach ◽

Antigen Presenting

Abstract BACKGROUND Despite recent advances in tumor immunotherapy in solid tumors, success in GBM remains elusive, likely due to its poor immunogenicity and CNS barriers limiting immune cell trafficking. Here we describe a novel approach of stimulating glioma-specific immunity by transdifferentiating GBM cells in situ to induced dendritic cells (iDCs). METHODS We applied NETZEN, an integrated deep-learning and gene network-based ranking computational platform and identified cell fate determinants (CFDs) to convert GBM cells to DCs. CFDs were delivered using a viral vector. Transdifferentiation was assessed by immunophenotyping and iDCs functionally validated by their ability to prime naive T cells. RESULTS A four CFDs subnetwork anchored by PU.1 was sufficient to transdifferentiate mouse GBM cells to CD45+MHCII+ cells with high co-stimulatory CD80 expression and to induce nearly 98% of GBM cells to express 100-fold higher levels of MHCI. Consistent with a new identity of antigen-presenting cells (APC), the induced immune cells are growth arrested, exhibit 3-fold higher phagocytic activity and upregulate the canonical antigen processing and presenting machineries by 10-40 folds, resulting in 40-fold greater efficiency at processing ovalbumin and presenting SIINFEKL on MHCI compared to native GBM cells. Importantly, SIINFEKL-loaded iAPCs are capable of activating naive OTII-CD4+ and OTI-CD8+ T cells, indicating that they are DC-like. In addition, iDCs efficiently present tumor cell-intrinsic antigens and elicit >20-fold higher activation and cytotoxicity in tumor-specific T cells compared to native GBM cells. Lastly, intratumoral GBM-DC transdifferentiation in a syngeneic orthotopic GBM model produces a robust memory T cell response in deep cervical draining lymph nodes compared to control animals. CONCLUSIONS Our results comfirm that GBM-derived iDCs acquire functions similar to native DCs, and thus, lay the foundation for a novel therapeutic approach in which poorly immunogenic tumors like GBM may be forced to generate their own immunity from within through cell fate transdifferentiation.

Download Full-text