Th17 cell heterogeneity in tissue inflammation

Abstract

IL-17-producing CD4+ T cells (Th17 cells) are key drivers of the pathogenesis of multiple autoimmune and inflammatory disorders. At the same time, Th17 cells have been found to play an important role in tissue homeostasis, especially at mucosal sites. The mechanisms by which Th17 cells mediate these diverse functions remain unknown. Revealing Th17 cell heterogeneity, plasticity, and its molecular regulation is important to design therapies that can specifically target pathogenic Th17 cells while leaving the beneficial population unharmed. To reveal in vivo Th17 cell heterogeneity, we performed combined fate mapping with profiling of the transcriptomes and TCR clonotypes of tissue Th17 cells at homeostasis and during autoimmune inflammation of the central nervous system (CNS). We identified two different populations of Th17 cells that are generated during an autoimmune reaction - one that is highly pro-inflammatory and expresses CXCR6 and traffics to CNS to induce neuroinflammation and another small population of Th17 cells that expresses SLAMF6 and is present during homeostasis. This non-pathogenic, stem-like SLAMF6+ population that traffics to the intestine, acts as a ready reservoir for the generation of the pathogenic CXCR6+ T cell population. Our results reveal a direct in vivo relationship between non-pathogenic and pathogenic Th17 populations. To analyze the molecular regulation of Th17 heterogeneity, we performed combined ATAC-seq and RNA-seq of non-pathogenic and pathogenic Th17 populations. We discovered substantial differences in the chromatin landscape of non-pathogenic and pathogenic Th17 cells and observed similarities of non-pathogenic Th17 cells and regulatory T cells, and pathogenic Th17 cells and Th1 cells. By integrating single-cell ATAC-seq and single-cell RNA-seq, we inferred a regulatory network of Th17 heterogeneity and predicted transcription factors that shape chromatin landscape of Th17 cell heterogeneity. We validated the transcription factor BACH2 as a novel regulator that drives homeostatic, stem-like Th17 programs while inhibiting pathogenic Th1-like programs in Th17 cells. In summary, our studies uncovered molecular mechanisms of Th17 cell heterogeneity that might apply to various autoimmune conditions. Our work provides a framework to leverage fate-mapping scRNA-seq data and chromatin profiles to yield a foundation for future explorations of novel drivers of Th17 pathogenicity.