4-1BB and the Epigenetic Regulations of This Molecule

4-1BB, a master regulator of our defense system, is present on several kinds of immune cells and has different functions in immune responses based on specific conditions. An expression of this molecule on T lymphocytes, antigen-presenting cells (APCs) and pathogenic cells directs immune responses by a costimulatory signal of 4-1BB and its ligand, 4-1BBL. Under abnormal conditions, such as inflammation and hypoxia, 4-1BB and 4-1BBL are also induced on nonimmune cells including epithelial cells, endothelial cells, smooth muscle cells, and cardiac myocytes. Recently, 4-1BB has been found on brite adipocytes; it is identified as a specific marker for this type of fat cells. An increase in acetylated histone by histone deacetylase inhibitors (HDACi) leads to an elevation of 4-1BB and 4-1BBL expression and major histocompatibility complex expression on T-cell lymphoma and other tumor cell lines, which enhance the activities of APCs and cytotoxic T lymphocytes to improve antitumor immune responses. Conversely, 4-1BB signaling triggered by a soluble 4-1BB receptor or anti-4-1BB antibodies strengthens the anticancer effect of HDACi by regulating both effector and regulatory T cells. Therefore, further investigations into the epigenetic regulations of 4-1BB/4-1BBL interaction will give us more meaningful information to develop new methods to prevent disorders in human beings such as cancer, obesity, autoimmune and infectious diseases.