Lineage Tracking the Generation of T Regulatory Cells From Microbial Activated T Effector Cells in Naïve Mice

Regulatory T cells (Tregs) are essential for the maintenance of gut homeostasis by suppressing conventional CD4⁺ helper T cells (Tconvs) that are activated by microbial antigens. Although thymus is the major source of the peripheral Tregs, peripheral conversion from Tconvs to Tregs have also been shown to occur under various experimental conditions. It remains less clear about the frequency of lineage conversion from Tconvs to Tregs in naïve animals. Here we used a newly established reporter system to track a group of post expansion Tregs (eTregs), which exhibited a stronger suppressive ability than the non-lineage marked Tregs. Notably, microbial antigens are the primary driver for the formation of eTregs. TCR repertoire analysis of Peyer's patch T cells revealed that eTregs are clonally related to Tconvs, but not to the non-lineage tracked Tregs. Adoptive transfer of Tconvs into lymphopenic hosts demonstrated a conversion from Tconvs to eTregs. Thus, our lineage tracking method was able to capture the lineage conversion from microbial activated effector T cells to Tregs in naïve animals. This study suggests that a fraction of clonally activated T cells from the natural T cell repertoire exhibits lineage conversion to Tregs in response to commensal microbes under homeostatic conditions.