Integrated single-cell transcriptomics and epigenomics reveals strong germinal center–associated etiology of autoimmune risk loci

Abstract

Description Single-cell ATAC sequencing maps the cell type–specific regulatory potential of transcription factors and autoimmune disease risk loci. Decoding autoimmune genetic risk Autoimmunity involves loss of immune tolerance that is normally maintained, in part, through tight regulation of germinal center (GC) responses. King et al. used single-cell sequencing to examine the gene expression and chromatin landscape of GC-rich human tonsils and predict the cell type–specific regulatory potential of autoimmune risk-associated genetic variants. After mapping tonsillar immune cell states and comparing with those found in bone marrow and peripheral blood, they found that fine-mapped autoimmune-associated SNPs were enriched in accessible chromatin detected only within tonsils, including GC-specific regulatory elements of IL21/IL21R, IL4R, and BCL6 and the transcription factors POU2AF1 and HHEX. This resource provides a cellular map of putative targets of genetic variation in autoimmune disease and highlights a key role for GC-specific regulation. The germinal center (GC) response is critical for both effective adaptive immunity and establishing peripheral tolerance by limiting autoreactive B cells. Dysfunction in these processes can lead to defective immune responses to infection or contribute to autoimmune disease. To understand the gene regulatory principles underlying the GC response, we generated a single-cell transcriptomic and epigenomic atlas of the human tonsil, a widely studied and representative lymphoid tissue. We characterize diverse immune cell subsets and build a trajectory of dynamic gene expression and transcription factor activity during B cell activation, GC formation, and plasma cell differentiation. We subsequently leverage cell type–specific transcriptomic and epigenomic maps to interpret potential regulatory impact of genetic variants implicated in autoimmunity, revealing that many exhibit their greatest regulatory potential in GC-associated cellular populations. These included gene loci linked with known roles in GC biology (IL21, IL21R, IL4R, and BCL6) and transcription factors regulating B cell differentiation (POU2AF1 and HHEX). Together, these analyses provide a powerful new cell type–resolved resource for the interpretation of cellular and genetic causes underpinning autoimmune disease.