Tissue-specific heterogeneity of Human T follicular helper cells marked by unique transcriptomes and regulatory architecture

Abstract T follicular helper (T FH) cells represent a distinct lineage of CD4 that engage with cognate B cells, facilitating the production high affinity vaccine- and pathogen-specific antibodies. In humans, FHcells can be detected in several tissues throughout body, each representing unique cellular environment complete signaling molecules. Despite FHcell importance to human health, it remains unclear if how anatomical location results diversity among FHcells. Here, we detail tissue-specific heterogeneity reflected both transcriptome chromatin architecture. sourced from circulating peripheral blood (cT FH), lung lymph nodes (lnT tonsils (tT an vitro differentiation model (exT were subjected RNA-sequencing ATAC-sequencing. When comparing expression conical FHgenes, including BCL6 PDCD1, spectrum magnitude emerged: cT FH< exT lnT tT FH. Increased accessibility at proximal cis-regulatory elements occurred within loci FHgenes similar tissue-dependent fashion correlated transcript levels. Additionally, gene signatures FHpopulation, presence transcription factor networks, implying tissue specific FHfunctionality. Integrating PageRank scRNA-seq revealed BCL-6, ASCL2, TOX, TOX2, AIOLOS as potential regulators FHgene program. Collectively, these findings amongst FHcells, while highlighting key developmental networks which could influence design future immunological therapies targeting Supported by grants NIH: (RO1 AI113021, F32 AI161857)