Ndfip1 mediates peripheral tolerance to self and exogenous antigen by inducing cell cycle exit in responding CD4⁺ T cells

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dc.contributor.authorAltin, J.
dc.contributor.authorDaley, S.
dc.contributor.authorHowitt, J.
dc.contributor.authorRickards, H.
dc.contributor.authorBatkin, A.
dc.contributor.authorHorikawa, K.
dc.contributor.authorPrasad, S.
dc.contributor.authorNelms, K.
dc.contributor.authorKumar, S.
dc.contributor.authorWu, L.
dc.contributor.authorTan, S.
dc.contributor.authorCook, M.
dc.contributor.authorGoodnow, C.
dc.date.issued2014
dc.description.abstractThe NDFIP1 (neural precursor cell expressed, developmentally down-regulated protein 4 family-interacting protein 1) adapter for the ubiquitin ligase ITCH is genetically linked to human allergic and autoimmune disease, but the cellular mechanism by which these proteins enable foreign and self-antigens to be tolerated is unresolved. Here, we use two unique mouse strains—an Ndfip1-YFP reporter and an Ndfip1-deficient strain—to show that Ndfip1 is progressively induced during T-cell differentiation and activation in vivo and that its deficiency causes a cell-autonomous, Forkhead box P3-independent failure of peripheral CD4+ T-cell tolerance to self and exogenous antigen. In small cohorts of antigen-specific CD4+ cells responding in vivo, Ndfip1 was necessary for tolerogen-reactive T cells to exit cell cycle after one to five divisions and to abort Th2 effector differentiation, defining a step in peripheral tolerance that provides insights into the phenomenon of T-cell anergy in vivo and is distinct from the better understood process of Bcl2-interacting mediator of cell death-mediated apoptosis. Ndfip1 deficiency precipitated autoimmune pancreatic destruction and diabetes; however, this depended on a further accumulation of nontolerant anti-self T cells from strong stimulation by exogenous tolerogen. These findings illuminate a peripheral tolerance checkpoint that aborts T-cell clonal expansion against allergens and autoantigens and demonstrate how hypersensitive responses to environmental antigens may trigger autoimmunity.
dc.description.statementofresponsibilityJohn A. Altin, Stephen R. Daley, Jason Howitt, Helen J. Rickards, Alison K. Batkin, Keisuke Horikawa, Simon J. Prasad, Keats A. Nelms, Sharad Kumar, Lawren C. Wu, Seong-Seng Tan, Matthew C. Cook, and Christopher C. Goodnow
dc.identifier.citationProceedings of the National Academy of Sciences of USA, 2014; 111(6):2067-2074
dc.identifier.doi10.1073/pnas.1322739111
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.orcidKumar, S. [0000-0001-7126-9814]
dc.identifier.urihttp://hdl.handle.net/2440/82612
dc.language.isoen
dc.publisherNatl Acad Sciences
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/585490
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1016953
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/427620
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1009190
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1002863
dc.rightsCopyright status unknown
dc.source.urihttps://doi.org/10.1073/pnas.1322739111
dc.subjectImmunological tolerance
dc.subjectallergy
dc.subjectT lymphocyte
dc.subjectInterleukin-4
dc.subjectAire (Autoimmune Regulator)
dc.titleNdfip1 mediates peripheral tolerance to self and exogenous antigen by inducing cell cycle exit in responding CD4⁺ T cells
dc.title.alternativeNdfip1 mediates peripheral tolerance to self and exogenous antigen by inducing cell cycle exit in responding CD4(+) T cells
dc.typeJournal article
pubs.publication-statusPublished

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