In autoimmunity, the mechanisms that guarantee that our defense system does not attack our own body – tolerance to oneself – does not work properly. Multiple sclerosis, which affects one in every 1,000 people in Spain, is a serious autoimmune disease in which the immune system attacks the myelin sheath of some types of neurons, causing progressive neurological disability.
Dr. Esteban Ballestar, leader of the Epigenetics and immune diseases group at the Josep Carrreras Leukaemia Research Institute, and Dr. Eva Martínez-Cáceres, leader of the Immunopathology group at the IGTP-Hospital Germans Trias i Pujol, have recently published in the journal Cell Reports the mechanism by which vitamin D activates the tolerance program of dendritic cells.
Dendritic cells are a type of immune cells present in the blood and tissues, capable of detecting potential threats and displaying them to lymphocytes in the lymph nodes. Once there, they decide whether the system is going to tolerate that threat or attack it.
It is known that when dendritic cells are treated with vitamin D, they develop tolerogenic characteristics, so treatment with tolerant dendritic cells in multiple sclerosis patients could slow the progression of the disease.
A growing number of experiments in animal models support this hypothesis and, as a matter of fact, the Neuroimmunology group of the Hospital Germans Trias i Pujol is carrying out an international clinical trial to check it in patients with multiple sclerosis. This trial is part of the European-funded project ReSToRe (www.h2020restore.eu/).
The article published in Cell Reports, by main authors Dr. Francesc Català-Moll, Anna Ferreté Bonastre and Gerard Godoy-Tena, concludes that the binding of the vitamin D receptor with the STAT3 protein results in the activation of TET2, a DNA demethylating agent – a type of epigenetic mark – that, in dendritic cells, promotes the activation of tolerance genes.
Thus, the researchers manage to demonstrate, for the first time, that the relationship between vitamin D and the generation of the tolerance profile of dendritic cells is due to the modification of epigenetic marks by TET2, through the IL-6- JAK-STAT3, very well-known clinical target.
With this new information, a door opens to the use of existing drugs that interfere with the STAT3 pathway and optimize the production of tolerogenic dendritic cells, capable of stopping the progression of multiple sclerosis and other autoimmune diseases.
This would be a new example of a promising cellular therapy, such as the CAR-T developed against cancer.
In the last years, tolerogenic dendritic cells (tolDC) have become one of the most promising alternatives for the treatment of autoimmune diseases, such as multiple sclerosis (MS), rheumatoid arthritis, or type 1 diabetes. In fact, several Phase I clinical trials have already finished or are currently ongoing, with positive results regarding the safety and the tolerability of this therapeutic cell-based approach (1).
In general, tolDC are commonly defined as a stable and semi-mature subset of dendritic cells (DC), between antigen-capturing immature DC (iDC) and immunogenic mature DC (mDC)—characterized by their increased expression of MHC class II and co-stimulatory molecules. But most importantly, tolDC are presumably capable to induce immune tolerance towards the peptides these cells are presenting, in an antigen-specific manner (2–5).
TolDC can be generated in vitro from peripheral blood monocytes. In the last years, a wide variety of protocols for their production have been reported, ranging from the use of different drugs and chemical agents to genetic engineering techniques (6, 7).
In this regard, the use of 1,25-dyhydroxyvitamin D3, the active form of vitamin D3, constitutes one of the most widely studied approaches for the differentiation of tolDC. Briefly, vitamin D3-induced tolDC (vitD3-tolDC) are thought to develop their regulatory properties through a semi-mature profile, their ability to inhibit or reduce T cell responses, and a switch of the immune response towards a TH2 profile (8–18). Furthermore, vitD3-tolDC are characterized by a reduced NF-κB-mediated activity and an increase of mTOR-mediated glucose metabolism (10, 19).
Even though tolDC—and vitD3-tolDC in particular—have been characterized with a developing knowledge over their metabolism, molecular mechanisms, and functional pathways, the specific effect of these cells over the rest of the immune-related components still remains elusive. It is known that tolDC can usually induce either anergy, hyporesponsiveness or depletion over activated T cells, as well as regulatory T cell (Treg) differentiation (20).
However, to our knowledge, so far only one study has focused its attention on the actual processes that autologous T cells might be undergoing upon tolDC interaction—reporting an induction of hyporesponsiveness of CD4+ memory and naïve T cells towards antigen-specific stimulation mediated by dexamethasone-induced tolDC (21)—but neither at the transcriptomic level nor with vitD3-tolDC in particular.
In previous studies, our group has already extensively characterized vitD3-tolDC phenotypically, functionally, and transcriptomically, evidencing the regulatory potential of these cells both in vitro and in vivo in the animal model of MS, experimental autoimmune encephalomyelitis (EAE) (13, 16, 22–24). Consequently, we wanted to take one step further for the elucidation of the mechanisms of immune tolerance induction of vitD3-tolDC.
With that aim, here we present a full phenotypical, functional, and transcriptomic characterization of T CD4+ cells after their interaction with autologous vitD3-tolDC loaded with tetanus toxin (TT), in order to study the antigen-specific effect mediated by these cells compared to TT-loaded immunogenic mDC.
The purpose of this study is to identify one or several potential biomarkers of the immune modulation developed by vitD3-tolDC over T cells, which could constitute an interesting tool for the monitoring of patients treated with these cells in clinical trials, and the understanding of the mechanisms of tolerance induction.
reference link :https://www.frontiersin.org/articles/10.3389/fimmu.2020.599623/full
More information: Francesc Català-Moll et al, Vitamin D receptor, STAT3, and TET2 cooperate to establish tolerogenesis, Cell Reports (2022). DOI: 10.1016/j.celrep.2021.110244