In immunology, fibroblasts play a decisive role in self-tolerance, not least because of their supply of different self-antigens. A research group from Tokyo has come to this conclusion.
From my medical studies, I can still remember that fibroblast cells are of mesenchymal origin and play a decisive role in the formation and breakdown of the extracellular matrix. They are a major component of human connective tissue. If the extensions of different fibroblasts connect with each other, zonulae occludentes are formed. They can synthesize collagen fibers and break them down again by producing collagenases. Fibroblasts also have the ability to phagocytize. They play a central role in the processes of wound healing. In today's article, we learn about the role of fibroblasts in self-tolerance.
Self-tolerance means that the immune system does not react to the body's own antigens. The central tolerance has its origin in the thymus. There, during the development of T-lymphocytes, those T-lymphocyte cell lines are negatively selected which can potentially react to the body's own antigens. This leads to clonal deletion. However, not all self-antigens occurring in the human body are represented in the thymus. Peripheral tolerance is based on 3 mechanisms and ensures that autoreactive differentiated T lymphocytes become inactivated or apoptotic through anergy, deletion, or suppression.1
Lymphotoxin plays a crucial role in self-tolerance. So far, the exact mechanism has not been clarified. Lymphotoxin - also known as tumor necrosis factor-beta - is a protein produced by activated T-lymphocytes to destroy tumor cells. This effector molecule unfolds its effect after uptake into its target cell. It also plays a role in fighting intracellular bacteria. The lymphotoxin beta receptor is essential for the physiological development of the immune system. It is involved in processes of T-lymphocyte maturation and modulation of the thymic microenvironment.2
The fibroblasts in the thymus seem to play a crucial role in the creation of central tolerance by producing different self-antigens. In the study, surface markers of medullary fibroblasts of the thymus were identified by their transcriptome profiles in the mouse model. Medullary fibroblasts of the thymus were the stromal cells with the highest lymphotoxin beta receptor expression. The research group could show that maturation of medullary fibroblasts and gene expression of these cells is lymphotoxin-dependent. Lymphotoxin sources are thymocytes in development. The removal of the lymphotoxin beta receptor on fibroblasts of the thymus resulted in an autoimmune phenotype. This showed reduced expression of tissue and fibroblast-specific antigens. The research group was able to show in their mouse model that there is no self-tolerance without the lymphotoxin-beta-receptor on the medullary fibroblasts of the thymus.3
In the next article, we will learn about the connection between the immune system and the development of depression.4
References:
1. Janeway C. A. et al (2001). Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001.
2. The role of the lymphotoxin beta receptor in the natural immune response (2005). Biological and Medical Research Centre of the Heinrich Heine University Düsseldorf.
3. Nitta, T. et al (2020). Fibroblasts as a source of self-antigens for central immune tolerance. Nat Immunol 21, 1172-1180 (2020).
4. Papplardo J. L. et al. (2020). Transcriptomic and clonal characterisation of T cells in the human central nervous system. Science Immunology.