Co-stimulate or Co-inhibit Regulatory T Cells, Which Side to Go?

Co-stimulatory and co-inhibitory molecules direct the “second signal,” which largely determines the outcome of the “first signal” generated by the interaction of T cell receptor (TCR) with cognate MHC–peptide complex. The co-stimulatory and co-inhibitory signals are key mechanistic contributors to the regulation of adaptive immunity, especially the T cell–mediated immune response. Regulatory T cells (Tregs) are a special population of T cells, which unlike other T cells function as “attenuators” to suppress T cell immunity. Dysregulation of either the “second signal” or Tregs leads to an unbalanced immune system, which can result in a range of immune-related disorders, including autoimmune diseases, chronic infections, and tumors. In contrast, precise manipulation of these two systems offers tremendous clinical opportunities to treat these same diseases. Co-stimulatory and co-inhibitory molecules modulate immunity at molecular level, whereas Tregs delicately control the immune response at cellular level. Accumulating evidence has demonstrated that these two regulatory strategies converge and synergize with each other. This review discusses recent progress on the roles of co-stimulatory and co-inhibitory signals in the context of Tregs.