Interferon-y excess leads to pathogenic accumulation of follicular helper T cells and germinal centers

Abstract

Overactivity of the germinal center (GC) pathway resulting from accumulation of follicular helper T (Tfh) cells causes autoimmunity, underscoring the need to understand the factors that control Tfh cell homeostasis. Here we have identifed posttranscriptional repression of interferon-y (Ifng) mRNA as a mechanism to limit Tfh cell formation. By using the sanroque lupus model, we have shown that decreased Ifng mRNA decay caused excessive IFN-g signaling in T cells and led to accumulation of Tfh cells, spontaneous GC, autoantibody formation, and nephritis. Unlike ICOS and T-bet deficiency that failed to rescue several autoimmune manifestations, interferon-y receptor (IFN-gR) deficiency prevented lupus development. IFN-y blockade reduced Tfh cells and autoantibodies, demonstrating that IFN-y overproduction was required to sustain lupus-associated pathology. Increased IFN-yR signaling caused Bcl-6 overexpression in Tfh cells and their precursors. This link between IFN-y and aberrant Tfh cell formation provides a rationale for IFN-y blockade in lupus patients with an overactive Tfh cell-associated pathway.