Ndfip1 mediates peripheral tolerance to self and exogenous antigen by inducing cell cycle exit in responding CD4+ T cells
Date
2013-12-17
Authors
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
Journal Title
Journal ISSN
Volume Title
Publisher
National Academy of Sciences
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.
Description
Keywords
immunological tolerance, allergy, T lymphocyte, Interleukin-4, Aire (Autoimmune Regulator)
Citation
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Source
PNAS 11.6 (2013):2067–2074
Type
Journal article