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^low/- T cells, CD8⁺ CD45RC^low 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.