CD8 Tregs revisited: A heterogeneous population with different phenotypes and properties.

Regulatory T cells (Tregs) play a key role in the peripheral self-tolerance and preventing autoimmunity. While classical CD4 Foxp3 Tregs are well established, their CD8 counterparts are still controversial in many aspects including their phenotypic identity and their mechanisms of suppression. Because of these controversies and because of only a limited number of studies documenting the immunoregulatory function of CD8 Tregs in vivo, the concept of CD8 Tregs is still not unanimously accepted. We propose that any T-cell subset considered as true regulatory must be distinguishable from other cell types and must suppress in vivo immune responses via a known mechanism. In this article, we revisit the concept of CD8 Tregs by focusing on the characterization of individual CD8 T-cell subsets with proposed regulatory capacity separately. Therefore, we review the phenotype and function of CD8 FOXP3 T cells, CD8 CD122 T cells, CD8 CD28 T cells, CD8 CD45RC T cells, T cells expressing CD8αα homodimer and Qa-1-restricted CD8 T cells to show whether there is sufficient evidence to establish these subsets as bona fide Tregs. Based on the intrinsic ability of CD8 Treg subsets to promote immune tolerance in animal models, we elaborate on their potential use in clinics.