Th17 cells have been investigated in mice primarily for their contributions to autoimmune diseases. However, the pathways of differentiation of Th17 and related (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 RORγt. 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 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.
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 RORγt. This continuum includes cells preserved within the memory pool with potentials that reflect the early preferential activation of multiple over single lineages. The phenotypes and epigenomes of CCR6+ cells are stable across cell divisions under noninflammatory conditions. Nonetheless, activation in polarizing and nonpolarizing conditions can yield additional functionalities, revealing, respectively, both environmentally induced and imprinted mechanisms that contribute differentially across the type 17 continuum to yield the unusual plasticity ascribed to type 17 cells.
Previously, we found that human type-17 Th cells from blood are fully contained within the CCR6-expressing subset. We also found positive correlations between levels of expression of CCR6 and levels of other type-17 proteins such as IL-17A/F, IL-22, and CCL20, □□□ negative correlations of CCR6 expression with that of genes/proteins associated with non-type-17 (Th1, Th2, TFH) pathways. In the present study, analysis of single Th cells expressing various levels of CCR6 using cell sorting followed by RT-PCR revealed that 1) patterns of expression of individual type-17 genes differed, being either binary (all-or-none-like) or graded, 2) expression levels of type-17 genes were positively correlated with each other and negatively correlated with genes associated with non-type-17 lineages, 3) cells could be identified that co-expressed genes for both type-17 and non-type-17 lineages, and 4) these “multi-lineage” cells expressed intermediate/low as opposed to high levels of the lineage-specific genes. Our data suggest that acquisition of the type-17 (and non-type-17) phenotype(s) is not all or none, but rather that cells occupy many intermediate states in forming a highly heterogeneous memory population, that genes defining “opposing” lineages can be co-expressed, and that expression of genes associated with opposing lineages is extinguished in cells at the far end of the type-17 spectrum. These findings are consistent with pathways of human Th differentiation in vivo that allow for the co-expression of multiple potentials, each to a limited degree, early on, but that subsequently narrow as a single phenotype becomes fully expressed.
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