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|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|
|Citation:||Proceedings of the National Academy of Sciences of USA, 2014; 111(6):2067-2074|
|Publisher:||Natl Acad Sciences|
|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.|
Aire (Autoimmune Regulator)
|Rights:||Copyright status unknown|
|Appears in Collections:||Aurora harvest 4|
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