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 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.

Pregnancy Enables Expansion of Disease-Specific Regulatory T Cells in an Animal Model of Multiple Sclerosis

“…This can be appreciated in the clear clustering by cell type in CDR3 amino acid-based multidimensional scaling and the heatmap of EAE clonotypes, which identifies distinct clonotype usage in Tcon and Treg. These observations are in line with previous work, showing that Tcon and Treg strongly differ in clonal composition (23,41), indicating that they are recruited from different clonal pools during thymic development (42) and that trans-differentiation between both subtypes is limited (23).…”

Foxp3 Molecular Dynamics in Treg in Juvenile Idiopathic Arthritis

“…Given this observation, it will be intriguing for future studies to interrogate relationships between the TCR repertoires of Th17 and Treg cells within the joints of O-JIA patients, in order to establish whether the reciprocal relationship arises from discrete clones, or whether Th17/Treg plasticity is an important mechanism. For instance hybrid IL-17A + FOXP3 + Treg, identified by expression of CD161, are significantly enriched at the site of inflammation ( 37 , 38 ), and repertoire overlap between CD161 + Treg and Tconv as a proportion of CD161 + SF Treg was in the region of 20–30% ( 38 ), suggesting plasticity of T-cell responses within the joint. In summary, what these papers clearly show is that the joint environment is highly dynamic, and that snapshot in time analyses may obscure observations that may be accounted for by cellular and molecular dynamics.…”

The role of chemokine receptor 9/chemokine ligand 25 signaling: From immune cells to cancer cells (Review)

“…Furthermore, several other studies demonstrated that DCs produced RA, which mediated CCR9 expression in T cells ( 25 ) and induced interleukin 10 (IL-10) expression in α4β7 + CCR9 + T cells ( 26 ). T cells were also mediated by RA directly via the RA receptor, which upregulated CCR9 expression ( 27 , 28 ). Therefore, decreased expression of the RA receptor was associated with a reduction in CCR9 expression and an attenuation of graft-versus-host disease ( 29 ).…”