The expanding family of noncanonical regulatory cell subsets

The overwhelming body of research on regulatory lymphocytes has focused on CD4(+) CD25(+) Foxp3(+) T cells (regulatory T cells); however, the last 5 years have witnessed inspiring progress in our understanding of regulatory B cells, regulatory CD8(+) T cells, regulatory gamma delta cells, and, more recently, regulatory innate lymphoid cells(ILCregs). This review focuses on these so-called noncanonical regulatory cell subsets. We primarily survey existing information on the phenotype, function, sustaining factors, and clinical value of the 4 best-characterized non-CD4 (+)Foxp3(+) T regulatory cells. We then take a brief journey into the advances and challenges associated with next-generation sequencing technologies and the application of sequencing to the study of noncanonical regulatory cell subsets.