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Type: Journal article
Title: Ndfip1 mediates peripheral tolerance to self and exogenous antigen by inducing cell cycle exit in responding CD4⁺ T cells
Other Titles: Ndfip1 mediates peripheral tolerance to self and exogenous antigen by inducing cell cycle exit in responding CD4(+) T cells
Author: Altin, J.
Daley, S.
Howitt, J.
Rickards, H.
Batkin, A.
Horikawa, K.
Prasad, S.
Nelms, K.
Kumar, S.
Wu, L.
Tan, S.
Cook, M.
Goodnow, C.
Citation: Proceedings of the National Academy of Sciences of USA, 2014; 111(6):2067-2074
Publisher: Natl Acad Sciences
Issue Date: 2014
ISSN: 0027-8424
Statement of
John 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
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.
Keywords: Immunological tolerance
T lymphocyte
Aire (Autoimmune Regulator)
Rights: Copyright status unknown
DOI: 10.1073/pnas.1322739111
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