Follicular T Cells are Clonally and Transcriptionally Distinct in B Cell-Driven Autoimmune Disease

Abstract

Pathogenic autoantibodies contribute to tissue damage and clinical decline in autoimmune disease. Follicular T cells are central regulators of germinal centers, although their role in epitope spreading towards autoantigens remains unclear. We performed single cell RNA and T cell receptor (TCR) sequencing of follicular T cells in autoantibody-mediated disease, allowing for analyses of paired transcriptomes and unbiased TCRαβ repertoires at single cell resolution. A minority of clonotypes were preferentially shared amongst autoimmune follicular T cells, and clonotypic expansion was associated with differential gene signatures in autoimmune disease. Antigen prediction using algorithmic and machine learning approaches revealed convergence towards shared specificities between non-autoimmune and autoimmune follicular T cells. However, differential autoimmune transcriptional signatures were preserved even amongst follicular T cells with shared predicted specificities. These results demonstrate that follicular T cells are phenotypically distinct in B cell-driven autoimmune disease, providing potential therapeutic targets to modulate autoreactive epitope spreading.