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

Sau K. Lee, Diego G. Silva, Jaime L. Martin, Alvin Pratama, Xin Hu, Pheh Ping Chang, Giles Walters, Carola G. Vinuesa*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

211 Citations (Scopus)

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-γ (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-γ 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-γ receptor (IFN-γR) deficiency prevented lupus development. IFN-γ blockade reduced Tfh cells and autoantibodies, demonstrating that IFN-γ overproduction was required to sustain lupus-associated pathology. Increased IFN-γR signaling caused Bcl-6 overexpression in Tfh cells and their precursors. This link between IFN-γ and aberrant Tfh cell formation provides a rationale for IFN-γ blockade in lupus patients with an overactive Tfh cell-associated pathway.

Original languageEnglish
Pages (from-to)880-892
Number of pages13
JournalImmunity
Volume37
Issue number5
DOIs
Publication statusPublished - 16 Nov 2012

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