title: Interferon-γ 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-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.
authors.affiliation: Department of Pathogens and Immunity, John Curtin School of Medical Research, The Australian National University, Acton, ACT 2601, Australia.
authors.forename: Sau K
authors.initials: SK
authors.lastname: Lee
authors.forename: Diego G
authors.initials: DG
authors.lastname: Silva
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Martin
authors.forename: Alvin
authors.initials: A
authors.lastname: Pratama
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.forename: Pheh-Ping
authors.initials: PP
authors.lastname: Chang
authors.forename: Giles
authors.initials: G
authors.lastname: Walters
authors.forename: Carola G
authors.initials: CG
authors.lastname: Vinuesa
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D005260:Female; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009393:Nephritis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000096743:Interferon gamma Receptor
chemical_list: D001323:Autoantibodies; D007371:Interferon-gamma; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor