T Cell Help Shapes B Cell Tolerance

Abstract

Maintenance of B cell tolerance allows organisms to defend against pathogens without attacking their own tissues. Loss of B cell tolerance leads to autoimmune disease driven by the accumulation of pathogenic autoantibodies. Over time these antibodies may evolve specificities against a range of autoantigens, termed epitope spreading. While T cell help is critical for humoral immunity, whether helper T cells promote or prevent loss of B cell tolerance and ensuing epitope spreading is unknown. Here we combine mouse models of autoimmunity, high-throughput single cell sequencing technologies, and manipulation of the follicular T cell repertoire to study how T cell help influences B cell tolerance. Single cell RNA and T cell receptor (TCR) sequencing of follicular T cells in a mouse model of autoantibody-mediated disease revealed that clonotypic expansion is associated with differential gene signatures in autoimmune disease. Machine learning prediction of antigen specificities surprisingly suggested convergence towards shared specificities between non-autoimmune and autoimmune follicular T cells despite differential autoimmune transcriptional signatures. Using genetic models of follicular T cell deficiency, we discovered that loss of B cell tolerance is dependent not only on the presence of T cell help, but also follicular TCR specificity. We identified cognate autoantigens of orphan follicular TCRs by peptidome-wide screening and demonstrate that individual autoreactive TCRs could narrow epitope spreading to a unique set of autoantigens identified by bead-based screening array. Therefore, TCR-dependent T cell help is necessary and sufficient to promote loss of B cell tolerance and epitope spreading. Improved understanding of T cell control of B cell tolerance may extend not only to autoantibody disease, but also to situations of evolving antibody specificity, such as cancer, multiple sclerosis, and COVID-19.