Abstract
Pathogenic autoantibodies contribute to tissue damage and clinical decline in autoimmune disease. Follicular T cells are central regulators of germinal centers, although their contribution to autoantibody-mediated disease remains unclear. Here we perform single cell RNA and T cell receptor (TCR) sequencing of follicular T cells in a mouse model of autoantibody-mediated disease, allowing for analyses of paired transcriptomes and unbiased TCRαβ repertoires at single cell resolution. A minority of clonotypes are preferentially shared amongst autoimmune follicular T cells and clonotypic expansion is associated with differential gene signatures in autoimmune disease. Antigen prediction using algorithmic and machine learning approaches indicates convergence towards shared specificities between non-autoimmune and autoimmune follicular T cells. However, differential autoimmune transcriptional signatures are 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 autoantibody development.
Highlights
Pathogenic autoantibodies contribute to tissue damage and clinical decline in autoimmune disease
These results demonstrate that in the presence of an autoreactive B cell clone follicular T cells adopt a transcriptionally distinct phenotype that is reflected in the T cell receptor (TCR) repertoire
B-cell driven autoimmune disease is established by reconstituting irradiated wild type mice with congenic wild type (WT) bone marrow mixed with bone marrow from 564Igi mice[3], which have heavy and light chain knock in of an autoreactive B cell receptor against ribonuclear complexes[9]
Summary
Pathogenic autoantibodies contribute to tissue damage and clinical decline in autoimmune disease. Reconstitution of irradiated wild type mice with bone marrow containing a single autoreactive B cell clone is capable of initiating multiorgan autoimmune disease These mice develop autoantibodies against the initial self-antigen, ribonucleoprotein, and an array of unrelated self-antigens such as A proliferation-inducing ligand (APRIL), bactericidal permeability increasing protein (BPI), and glomerular basement membrane (GBM), leading to glomerular deposition of autoantibodies. Prediction of antigen binding using VDJ database annotation shows that this differential expression is preserved even amongst clonotypes with the same predicted specificities These results demonstrate that in the presence of an autoreactive B cell clone follicular T cells adopt a transcriptionally distinct phenotype that is reflected in the TCR repertoire
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