T cell receptors from CD8 regulatory T cells direct the development of natural intraepithelial lymphocytes

CD8 regulatory T cells (CD8 Tregs) in mice have been identified by their expression of the surface receptor family Ly49 and the transcription factor Helios. To our surprise, many Ly49+ and Helios+ T cells express neither CD4 nor CD8, and many express only CD8. We found that CD8 Tregs in the spleen are linked to the CD8{beta}- natural intraepithelial lymphocytes (IELs) that reside in the small intestine. Blocking trafficking to the intestine increased splenic CD8 Treg frequency, and transferred splenic CD8 Tregs gave rise to natural IELs. Unexpectedly, Helios was dispensable for natural IEL development, arguing against its role as a shared lineage-determining transcription factor. Instead, we found that T cell receptors (TCRs) from splenic Ly49+ CD8 Tregs deterministically direct natural IEL development. Our findings suggest that CD8 Tregs may derive from the same TCR-directed developmental program that generates natural IELs and shed light on the origins of these immunoregulatory cells.