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 α4(+)β7(+) 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 in vitro. 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.