CD161 Tconv and CD161 Treg Share a Transcriptional and Functional Phenotype despite Limited Overlap in TCRβ Repertoire.

Human regulatory T cells (Treg) are important in immune regulation, but can also show plasticity in specific settings. CD161 is a lectin-like receptor and its expression identifies an effector-like Treg population. Here, we determined how CD161 Treg relate to CD161 conventional T cells (Tconv). Transcriptional profiling identified a shared transcriptional signature between CD161 Tconv and CD161 Treg, which is associated with T helper (Th)1 and Th17 cells, and tissue homing, including high expression of gut-homing receptors. Upon retinoic acid (RA) exposure, CD161 T cells were more enriched for CCR9 and integrin α4β7 cells than CD161 T cells. In addition, CD161 Tconv and CD161 Treg were enriched at the inflamed site in autoimmune arthritis, and both CD161 and CD161 Treg from the inflamed site were suppressive . CD161 T cells from the site of autoimmune arthritis showed a diminished gut-homing phenotype and blunted response to RA suggesting prior imprinting by RA in the gut or at peripheral sites rather than during synovial inflammation. TCRβ repertoires of CD161 and CD161 Tconv and Treg from blood showed limited overlap whereas there was clear overlap between CD161 and CD161 Tconv, and CD161 and CD161 Treg from the inflamed site suggesting that the inflamed environment may alter CD161 levels, potentially contributing to disease pathogenesis.