Advances in the Study of CD8+ Regulatory T Cells

Immune tolerance mediated by CD4(+) and CD8(+) regulatory T (Treg) cells is important in the control of inflammatory and autoimmune diseases. Although CD4(+)FoxP3(+) Treg cells are well studied, our current knowledge of the biology of CD8(+) Treg cells has several critical gaps. A major limitation was our inability to distinguish them from conventional CD8(+)T cells. In this regard, we have recently discovered an innate-like PLZF(+)CD8 alpha alpha+TCR alpha beta(+) Treg population (CD8 alpha alpha Treg cells) that is enriched in the liver in naive mice and present in healthy humans. We have demonstrated that these CD8 alpha alpha Treg cells serve as a feedback regulatory mechanism and target only activated effector T cells. Such feedback regulation allows the progression of an immune defense response yet prevents excessive tissue damage. It is likely that the PLZF transcription program endows the CD8 alpha alpha Treg cells with the innate features that are important for them to effectively control autoimmune responses by targeting activated T cells in both mice and humans. Additional features of the CD8 alpha alpha Treg cells include their dependence on IL-15/IL-2R beta signaling, the expression of NK-inhibitory receptors, and the memory phenotype. Importantly, these cells are expanded following an ongoing immune response and serve as a feedback regulatory mechanism to control activated effector T cells, and hence prevent an excessive immune stimulation. In this review, we will briefly summarize recent important findings related to CD8(+) Treg cells.