Interferon-³ Excess Leads to Pathogenic Accumulation of Follicular Helper T Cells and Germinal Centers

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-³ (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-³ 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-³ receptor (IFN-³R) deficiency prevented lupus development. IFN-³ blockade reduced Tfh cells and autoantibodies, demonstrating that IFN-³ overproduction was required to sustain lupus-associated pathology. Increased IFN-³R signaling caused Bcl-6 overexpression in Tfh cells and their precursors. This link between IFN-³ and aberrant Tfh cell formation provides a rationale for IFN-³ blockade in lupus patients with an overactive Tfh cell-associated pathway. º Posttranscriptional repression of Ifng mRNA limits Tfh cell accumulation º IFN-³ signals act in T cells to increase Tfh cells and germinal centers º Excessive IFN-³R signaling leads to Bcl-6 overexpression in Tfh cells º IFN-³R deficiency and IFN-³ blockade reduces Tfh cells and prevents sanroque lupus