Ndfip1 mediates peripheral tolerance to self and exogenous antigen by inducing cell cycle exit in responding CD4+ T cells
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Altin, John A; Daley, Stephen R; Howitt, Jason; Rickards, Helen J; Batkin, Alison K; Horikawa, Keisuke; Prasad, Simon J; Nelms, Keats A; Kumar, Sharad; Wu, Lawren C; Tan, Seong-Seng; Cook, Matthew C; Goodnow, Christopher C
Description
The 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...[Show more]
dc.contributor.author | Altin, John A | |
---|---|---|
dc.contributor.author | Daley, Stephen R | |
dc.contributor.author | Howitt, Jason | |
dc.contributor.author | Rickards, Helen J | |
dc.contributor.author | Batkin, Alison K | |
dc.contributor.author | Horikawa, Keisuke | |
dc.contributor.author | Prasad, Simon J | |
dc.contributor.author | Nelms, Keats A | |
dc.contributor.author | Kumar, Sharad | |
dc.contributor.author | Wu, Lawren C | |
dc.contributor.author | Tan, Seong-Seng | |
dc.contributor.author | Cook, Matthew C | |
dc.contributor.author | Goodnow, Christopher C | |
dc.date.accessioned | 2014-02-20T23:43:13Z | |
dc.date.available | 2014-02-20T23:43:13Z | |
dc.identifier.issn | 1091-6490 | |
dc.identifier.other | ESSN:1091-6490 | |
dc.identifier.uri | http://hdl.handle.net/1885/11404 | |
dc.description.abstract | The 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.format | 8 pages | |
dc.publisher | National Academy of Sciences | |
dc.rights | http://www.sherpa.ac.uk/romeo/issn/1091-6490/ author can archive pre-print (ie pre-refereeing);author can archive post-print (ie final draft post-refereeing);author cannot archive publisher's version/PDF (Sherpa/Romeo as at 20/2/14) | |
dc.source | PNAS 11.6 (2013):2067–2074 | |
dc.subject | immunological tolerance | |
dc.subject | allergy | |
dc.subject | T lymphocyte | |
dc.subject | Interleukin-4 | |
dc.subject | Aire (Autoimmune Regulator) | |
dc.title | Ndfip1 mediates peripheral tolerance to self and exogenous antigen by inducing cell cycle exit in responding CD4+ T cells | |
dc.type | Journal article | |
local.identifier.citationvolume | 111 | |
dc.date.issued | 2013-12-17 | |
local.identifier.absfor | 110700 - IMMUNOLOGY | |
local.identifier.ariespublication | u4971216xPUB287 | |
local.publisher.url | http://www.nas.edu/ | |
local.type.status | Published Version | |
local.contributor.affiliation | Altin, John A, John Curtin School of Medical Research, Australian National University | |
local.contributor.affiliation | Daley, Stephen R, John Curtin School of Medical Research, Australian National University | |
local.contributor.affiliation | Rickards, Helen J, John Curtin School of Medical Research, Australian National University | |
local.contributor.affiliation | Batkin, Alison K, John Curtin School of Medical Research, Australian National University | |
local.contributor.affiliation | Horikawa, Keisuke, John Curtin School of Medical Research, Australian National University | |
local.contributor.affiliation | Prasad, Simon J, John Curtin School of Medical Research, Australian National University | |
local.contributor.affiliation | Nelms, Keats A, John Curtin School of Medical Research, Australian National University | |
local.contributor.affiliation | Cook, Matthew C, John Curtin School of Medical Research, Australian National University | |
local.contributor.affiliation | Goodnow, Christopher C, John Curtin School of Medical Research, Australian National University | |
dc.relation | http://purl.org/au-research/grants/nhmrc/585490 | |
dc.relation | http://purl.org/au-research/grants/nhmrc/1016953 | |
dc.relation | http://purl.org/au-research/grants/nhmrc/427620 | |
dc.relation | http://purl.org/au-research/grants/nhmrc/1009190 | |
dc.relation | http://purl.org/au-research/grants/nhmrc/1002863 | |
local.bibliographicCitation.issue | 6 | |
local.bibliographicCitation.startpage | 2067 | |
local.bibliographicCitation.lastpage | 2074 | |
local.identifier.doi | 10.1073/pnas.1322739111 | |
dc.date.updated | 2015-12-09T09:35:48Z | |
local.identifier.scopusID | 2-s2.0-84893856193 | |
local.identifier.thomsonID | 000330999600018 | |
Collections | ANU Research Publications |
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