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

Abstract

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 <i>in vitro</i>. 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.