April 30, 2012
Dr. Chikuma
The finding of the research team led by Professor Tasuku Honjo and Assistant Professor Shunsuke Chikuma of the Graduate School of Medicine was published on Nature Immunology.
Background
T-lymphocytes (T cells) provide powerful defense against pathogen and tumor. However, uncontrolled activation of T cells is a cause of serious autoimmune diseases (i.e. type I diabetes, thyroiditis, rheumatoid arthritis.) In healthy individuals, T cells are kept "naïve" until when they find enemies. Naïve T cells have to frequently interact with self-tissues to acquire "weak" survival signals, thus there must be inhibitory mechanisms to avoid their activation against self. Dynamic change in gene expression is known to occur during the activation of T cells, however, little is known about gene regulation and the factor that prevents the activation of naïve T cells against self.
Results
TRIM28 is a chromatin regulatory factor which regulates transcription of many genes through its association with histone methyltransferases and heterochromatin proteins. We found Ser473 residue within TRIM28 protein, which is known to work as on/off switch for gene regulation by TRIM28, was controlled by T cell’s survival signals at the level of phosphorylation. To understand the role of TRIM28 in T cells, we newly generated conditional knockout mice that lack TRIM28 specifically in T cells. These mice, when kept in pathogen free conditions, developed T cell mediated inflammation against various organs and died younger than normal mice. Naïve T cells eventually lost their “naiveness” and differentiated into memory-like T cells that produced inflammatory cytokine IL-17 against self tissue. At the mechanistic level, T cells lacking TRIM28 showed de-repression of immune-regulatory cytokines such as TGF beta, which altered systemic cytokine balance and thus caused autoimmunity. Our study, for the first time demonstrated an active gene silencing by an epigenetic factor is involved in T cell homeostasis and prevention of autoimmune diseases.