Altin, John ADaley, Stephen RHowitt, JasonRickards, Helen JBatkin, Alison KHorikawa, KeisukePrasad, Simon JNelms, Keats AKumar, SharadWu, Lawren CTan, Seong-SengCook, Matthew CGoodnow, Christopher C2014-02-202014-02-201091-6490ESSN:1091-6490http://hdl.handle.net/1885/11404The 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.8 pageshttp://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)immunological toleranceallergyT lymphocyteInterleukin-4Aire (Autoimmune Regulator)Ndfip1 mediates peripheral tolerance to self and exogenous antigen by inducing cell cycle exit in responding CD4+ T cells2013-12-1710.1073/pnas.13227391112015-12-09