Research on Controlling Cellular Outposts of the Immune System

Research on how to control cellular outposts of the immune system
A small RNA molecule in dendritic cells regulates our immune system

Date of Release: 12 May 2021

Graz: Every day, the immune system must work at maximum capacity to protect the body from disease. Dendritic cells (DCs) are highly specialized defense cells that are regarded as the cellular outposts of the immune system. Med Uni Graz scientists have investigated how the immune system can tolerate harmless cells while inducing immunity to pathogens. The findings have been published in the internationally renowned journal “Cell Reports.”

Outposts of the immune system as the focus of research at Med Uni Graz

Dendritic cells are found in many organs and tissues. Certain subtypes of DCs in epithelia (epidermis, mucous membranes in the intestines and lungs) prevent exaggerated immune reponses to useful microbes and environmental substances, for example those we ingest from food. They are equipped with a variety of receptor structures for environmental molecules and microbes and are capable of moving into lymphoid tissue, where they induce antigen-specific T-cell responses and can suppress the immune response or cause immune tolerance. This type of dendritic cell is also referred to as a regulatory or tolerogenic DC; in contrast, an inflammatory or immunogenic DC is capable of inducing a protective immune response. At the Otto Loewi Research Center at Med Uni Graz, a study conducted by Herbert Strobl of the Division of Immunology and Pathophysiology and PhD student Victoria Zyulina in close cooperation with Jose M. Silva of Icahn School of Medicine at Mount Sinai, New York, attempted to shed light on the mechanism underlying the development of DCs with tolerogenic versus immunogenic properties.

Investigating the helpers of the immune system: Mechanisms still largely unknown

To protect health, immune responses normally provide an effective line of defense against pathogens. If the immune response is directed against harmless antigens or if inappropriate or excessive responses are triggered, the result is an exaggerated immune response that becomes noticeable in allergies, autoimmune disease or chronic inflammatory bowel disease. Little research has been conducted on how DCs interact with environmental signals to develop an appropriate immune response to pathogens while preventing an inappropriate or excessive immune response. “We know that DCs are responsible for effective immune responses to microbes such as dangerous viruses. The body accomplishes this through the generation of specialized DC subsets as well as through biochemical signals,” explains Herbert Strobl. The epithelia of the skin and mucous membranes contain Langerhans cells (LC), a subtype of immune cells that possesses tolerogenic properties as well as the ability to renew itself. The tissues below and inflammatory lesions contain cells with proinflammatory properties called moDCs, or monocyte-derived dendritic cells.

Importance of microRNAs: Regulation of processes in cells and tissues

RNA molecules are highly important in the biosynthesis of protein molecules. Protein-coding RNA molecules were recently employed to develop a vaccine against COVID-19. However, RNA molecules can also exhibit negative regulatory effects. In 2006 a Nobel Prize was awarded for the discovery of the process of RNA interference. Over the past 20 years, it has become apparent that many important biological processes in cells and tissues are regulated by microRNAs—small non-coding RNAs. A flaw in the biosynthesis of these microRNAs leads to abnormal development and function of DCs. The researchers concentrated on the molecular mechanisms regulated by specific microRNAS in the development of DC subsets. They specifically looked for microRNAs formed by the DC subsets mentioned above (LC versus MoDC). It turned out that miR-424(322)/503 is much more highly regulated in proinflammatory moDCs than in LCs. “Using gene transfer techniques, we determined that miR-424(322)/503 is critical to the development of moDC. Conversely, the development of LCs was not limited by a lack of miR-424(322)/503,” explains Herbert Strobl. In addition, moDC subgroups in the skin of mice that lacked miR-424 (322)/503 were significantly reduced under inflammatory conditions as compared to normal mice. “The data confirmed our studies of human cells that indicated that the differentiation of moDCs from LCs is dependent on miR-424 (322)/503,” says Victoria Zyulina.

Gene cluster regulated pro- vs. anti-inflammatory DC subset differentiation

Finally, the scientists determined that genes in the TGF-beta signaling pathway are highly regulated in DC precursor cells. In accordance with this, the loss of miR-424/503 in DC precursor cells favors TGF-beta1-dependent LC differentiation at the expense of moDC differentiation. “That is why we proposed a model in which miR-424(322)/503 functions as a molecular switch that uses modulation of TGF-beta signaling to decide whether tolerogenic/anti-inflammatory LCs or proinflammatory moDCs are formed,” says Zyulina. The clarification of this mechanism has contributed to the understanding of how our immune system can induce tolerance to harmless molecules and microbes while inducing immunity to dangerous pathogens. Follow-up studies will show whether a therapeutic intervention targeting this switch provides an opportunity to regulate abnormal immune responses in allergies, autoimmune diseases and malignancies.

Further information and contact

Herbert Strobl

Victoria Zyulina

Medical University of Graz, Otto Loewi Research Center, Division of Immunology and Pathophysiology

Tel.: +43 676 7576 195

herbert.strobl@medunigraz.at

viktoria.zyulina@medunigraz.at

Profile: Herbert Strobl and Victoria Zyulina

Herbert Strobl works with a variety of experimental methods to investigate the immune system. Together with Victoria Zyulina, who started the FWF sponsored PhD program DK-MOLIN at Med Uni Graz after completing her medical education in Russia, he would like to achieve a better understanding of these processes in order to develop new therapeutic strategies for diseases such as autoimmune diseases, allergies and cancer.

Link to publication: The miR-424(322)/503 gene cluster regulates pro- vs anti-inflammatory skin DC subset differentiation by modulating TGF-beta signaling
https://www.cell.com/cell-reports/fulltext/S2211-1247(21)00365-X