Interferon-y excess leads to pathogenic accumulation of follicular helper T cells and germinal centers
Date
2012-11-16
Authors
Lee, Sau K
Silva, Diego G
Martin, Jaime L
Pratama, Alvin
Hu, Xin
Chang, Pheh Ping
Walters, Giles
Vinuesa, Carola
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier (Cell Press)
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.
Description
Keywords
overactivity, germinal center, autoimmunity, follicular helper T cells
Citation
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Source
Immunity 37.5 (2012): 880–892
Type
Journal article