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

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.

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TIGIT-Fc as a Potential Therapeutic Agent for Fetomaternal Tolerance

Frontiers in Immunology ◽

10.3389/fimmu.2021.649135 ◽

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.

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Transfection of Vitamin D3-Induced Tolerogenic Dendritic Cells for the Silencing of Potential Tolerogenic Genes. Identification of CSF1R-CSF1 Signaling as a Glycolytic Regulator

International Journal of Molecular Sciences ◽

10.3390/ijms22147363 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7363

Author(s):

María José Mansilla ◽

Iñigo González-Larreategui ◽

Neus Figa-Martín ◽

Jaume Barallat ◽

Federico Fondelli ◽

...

Keyword(s):

Cell Proliferation ◽

Dendritic Cells ◽

Vitamin D3 ◽

Metabolic Reprogramming ◽

T Cell Proliferation ◽

Promising Strategy ◽

Tolerogenic Dendritic Cells ◽

Regulatory Properties ◽

Suppressive Mechanism

The use of autologous tolerogenic dendritic cells (tolDC) has become a promising strategy to re-establish immune tolerance in autoimmune diseases. Among the different strategies available, the use of vitamin D3 for the generation of tolDC (VitD3-tolDC) has been widely tested because of their immune regulatory properties. To identify molecules and pathways involved in the generation of VitD3-tolDC, we established an easy and fast gene silencing method based on the use of Viromer blue to introduce siRNA into monocytes on day 1 of culture differentiation. The analysis of the effect of CD209 (DC-SIGN) and CD115 (CSF1R) down-modulation on the phenotype and functionality of transfected VitD3-tolDC revealed a partial role of CD115 in their tolerogenicity. Further investigations showed that CSF1R-CSF1 signaling is involved in the induction of cell metabolic reprogramming, triggering glycolysis to produce high amounts of lactate, a novel suppressive mechanism of T cell proliferation, recently found in autologous tolerogenic dendritic cells (ATDCs).

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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.

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STAT3 Activation in Combination with NF-KappaB Inhibition Induces Tolerogenic Dendritic Cells with High Therapeutic Potential to Attenuate Collagen-Induced Arthritis

Journal of Immunology Research ◽

10.1155/2019/1982570 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Carolina Prado ◽

Valentina Ugalde ◽

Hugo González ◽

Alicia Figueroa ◽

Ernesto López ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Therapeutic Potential ◽

Collagen Induced Arthritis ◽

Tolerogenic Dendritic Cells ◽

Nf Kappab ◽

Stat3 Signalling ◽

Inflammatory Phenotypes ◽

Significant Therapeutic Effect ◽

Constitutively Active

Dendritic cells (DCs) have the ability to induce tolerance or inflammation in response to self-antigens, which makes them fundamental players in autoimmunity. In this regard, immunogenic DCs produce IL-12 and IL-23 favouring the acquisition of Th1 and Th17 inflammatory phenotypes, respectively, by autoreactive CD4+ T-cells, thus promoting autoimmunity. Conversely, tolerogenic DCs produce IL-10 and TGF-β, inducing the generation of CD4+ T-cells with suppressive activity (Treg), which promote tolerance to self-constituents. Previous studies have shown that STAT3 signalling in DCs attenuates the production of proinflammatory cytokines, whilst NF-κB activation promotes it. In this study, we aimed to generate DCs displaying strong and constitutive tolerogenic profile to be used as immunotherapy in autoimmunity. To this end, we transduced bone marrow-derived DCs with lentiviral particles codifying for a constitutively active version of STAT3 (constitutively active STAT3 (STAT3ca)) or with a constitutive repressor of NF-κB (IκBα superrepressor (IκBαSR)), and their therapeutic potential was evaluated in a mouse model of arthritis induced by collagen (CIA). Our results show that STAT3ca transduction favoured the production of the anti-inflammatory mediator IL-10, whereas IκBαSR transduction attenuated the expression of the proinflammatory cytokine IL-23 in DCs. Moreover, both STAT3ca-transduced and IκBαSR-transduced DCs separately exerted a mild but significant therapeutic effect reducing the severity of CIA development. Furthermore, when DCs were transduced with both STAT3ca and IκBαSR together, they reduced CIA manifestation significantly stronger than when transduced with only STAT3ca or IκBαSR separately. These results show STAT3 and NF-κB as two important and complementary regulators of the tolerogenic behaviour of DCs, which should be considered as molecular targets in the design of DC-based suppressive immunotherapies for the treatment of autoimmune disorders.

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