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

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

Description

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...[Show more]

dc.contributor.authorLee, Sau K
dc.contributor.authorSilva, Diego G
dc.contributor.authorMartin, Jaime L
dc.contributor.authorPratama, Alvin
dc.contributor.authorHu, Xin
dc.contributor.authorChang, Pheh Ping
dc.contributor.authorWalters, Giles
dc.contributor.authorVinuesa, Carola
dc.date.accessioned2014-02-19T23:32:53Z
dc.date.available2014-02-19T23:32:53Z
dc.identifier.issn1074-7613
dc.identifier.urihttp://hdl.handle.net/1885/11398
dc.description.abstractOveractivity 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.
dc.description.sponsorshipWe thank C. Gillespie for help in the preparation of electron microscopy slides, C.G.V. is supported by an Elizabeth Blackburn NHMRC fellowship. This work was funded by NHMRC program and project grants to C.G.V.
dc.format13 pages
dc.publisherElsevier (Cell Press)
dc.rightshttp://www.sherpa.ac.uk/romeo/issn/1074-7613/
dc.sourceImmunity 37.5 (2012): 880–892
dc.subjectoveractivity
dc.subjectgerminal center
dc.subjectautoimmunity
dc.subjectfollicular helper T cells
dc.titleInterferon-y excess leads to pathogenic accumulation of follicular helper T cells and germinal centers
dc.typeJournal article
local.identifier.citationvolume37
dcterms.dateAccepted2012-07-23
dc.date.issued2012-11-16
local.identifier.absfor110703 - Autoimmunity
local.identifier.absfor110705 - Humoural Immunology and Immunochemistry
local.identifier.absfor110704 - Cellular Immunology
local.identifier.ariespublicationf5625xPUB1983
local.publisher.urlhttp://www.cell.com/cellpress
local.type.statusPublished Version
local.contributor.affiliationLee, Sau K, Department of Pathogens and Immunity, John Curtin School of Medical Research, The Australian National University
local.contributor.affiliationSilva, Diego G, Department of Pathogens and Immunity, John Curtin School of Medical Research, The Australian National University
local.contributor.affiliationMartin, Jaime L, Department of Pathogens and Immunity, John Curtin School of Medical Research, The Australian National University
local.contributor.affiliationPratama, Alvin, Department of Pathogens and Immunity, John Curtin School of Medical Research, The Australian National University
local.contributor.affiliationHu, Xin, Department of Pathogens and Immunity, John Curtin School of Medical Research, The Australian National University
local.contributor.affiliationChang, Pheh Ping, Department of Pathogens and Immunity, John Curtin School of Medical Research, The Australian National University
local.contributor.affiliationWalters, Giles, The Australian National University Medical School
local.contributor.affiliationVinuesa, Carola G, Department of Pathogens and Immunity, John Curtin School of Medical Research, The Australian National University
local.bibliographicCitation.issue5
local.bibliographicCitation.startpage880
local.bibliographicCitation.lastpage892
local.identifier.doi10.1016/j.immuni.2012.10.010
local.identifier.absseo920116 - Skeletal System and Disorders (incl. Arthritis)
local.identifier.absseo920108 - Immune System and Allergy
dc.date.updated2015-12-10T11:28:31Z
local.identifier.scopusID2-s2.0-84869213212
local.identifier.thomsonID000311460000014
CollectionsANU Research Publications

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