Human CCR6+ Th cells show both an extended stable gradient of Th17 activity and imprinted plasticity [Spsingh-10xTCR-CMV]

Th17 cells have been investigated in mice primarily for their contributions to autoimmune diseases. However, the pathways of differentiation of Th17 and related Th cells (type 17 cells) and the structure of the type 17 memory population in humans are not well understood; such understanding is critical for manipulating these cells in vivo. By exploiting differences in levels of surface CCR6, we found that human type 17 memory cells, including individual T cell clonotypes, form an elongated continuum of type 17 character along which cells can be driven by increasing ROR?t. This continuum includes cells preserved within the memory pool with potentials that reflect the early preferential activation of multiple over single lineages. The CCR6+ cells' phenotypes and epigenomes are stable across cell divisions under homeostatic-like conditions. Nonetheless, activation in polarizing and non-polarizing conditions can yield additional functionalities, revealing, respectively, both environmentally induced and imprinted mechanisms that contribute differentially across the continuum to yield the unusual plasticity ascribed to type 17 cells. Overall design: Single cell TCR V-d-J sequencing of 4 T-cell subsets with graded levels of CCR6. Independent replicates from two donors. This experiment utilizes an enrichment of an anti-CMV sub-population of T-cells ,which decreases the TCR diversity such that shared clonotypes can be detected and tracked across the CCR6 subsets.