2021/02/24
Keio University School of Medicine
Japan Agency for Medical Research and Development
A joint research group—including Senior Lecturer Shunsuke Chikuma and Professor Akihiko Yoshimura of the Department of Microbiology and Immunology, Keio University School of Medicine; Associate Professor Soichiro Yamanaka of the Laboratory of RNA Biology, Department of Biological Sciences, Graduate School of Science, The University of Tokyo; Lecturer Satoru Nakagawa of the Department of Molecular Life Science, Tokai University School of Medicine; and Postdoctoral Fellow Mahoko Ueda (currently Assistant Professor, Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University)—has revealed that the nuclear molecule TRIM28 suppresses harmful gene expression in dendritic cells and inhibits excessive immune responses.
Immune responses are initiated when dendritic cells, which have captured "foreign substances" such as viruses, present "foreign antigens" to a very small number of antigen-specific T lymphocytes (T cells). If abnormalities occur in this process, known as antigen presentation, it can lead to insufficient or excessive activation of lymphocytes, potentially causing immunodeficiency or autoimmune diseases, respectively. Therefore, the function of dendritic cells must be strictly regulated.
The group found that in mice with a dendritic cell-specific deletion of TRIM28, excessive T cell activation and differentiation into inflammatory cells occurred, leading to severe disease in autoimmune disease models. A comprehensive genomic analysis of TRIM28-deficient dendritic cells revealed that some endogenous retroviruses (ERVs) scattered throughout the genome are transcribed into RNA without their usual suppression. It was found that these ERVs lead the body's immune system into an inflammatory state by being expressed as "foreign antigens" or by inducing the expression of nearby immune-related genes.
Furthermore, a decline in TRIM28 function and ERV expression were also observed in the immune system cells of naturally aged mice. This study sheds light on one aspect of the inflammatory phenotype that occurs in many aging individuals.
The results of this research were published in the American Association of Immunologists' journal, "The Journal of Immunology," on February 22, 2021 (US Eastern Time).
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