T cell signaling targets for enhancing regulatory or effector function

To respond to infection, resting or naïve T cells must undergo activation, clonal expansion, and differentiation into specialized functional subsets of effector T cells. However, to prevent excessive or self-destructive immune responses, regulatory T cells (T(regs)) are instrumental in suppressing the activation and function of effector cells, including effector T cells. The transcription factor Forkhead box P3 (Foxp3) regulates the expression of genes involved in the development and function of T(regs). Foxp3 interacts with other transcription factors and with epigenetic elements such as histone deacetylases (HDACs) and histone acetyltransferases. T(reg) suppressive function can be increased by exposure to HDAC inhibitors. The individual contributions of different HDAC family members to T(reg) function and their respective mechanisms of action, however, remain unclear. A study showed that HDAC6, HDAC9, and Sirtuin-1 had distinct effects on Foxp3 expression and function, suggesting that selectively targeting HDACs individually or in combination may enhance T(reg) stability and suppressive function. Another study showed that the receptor programmed death 1 (PD-1), a well-known inhibitor of T cell activation, halted cell cycle progression in effector T cells by inhibiting the transcription of the gene encoding the substrate-recognition component (Skp2) of the ubiquitin ligase SCF(Skp2). Together, these findings reveal new signaling targets for enhancing T(reg) or effector T cell function that may be helpful in designing future therapies, either to increase T(reg) suppressive function in transplantation and autoimmune diseases or to block PD-1 function, thus increasing the magnitude of antiviral or antitumor immune responses of effector T cells.