title: Ndfip1 mediates peripheral tolerance to self and exogenous antigen by inducing cell cycle exit in responding CD4+ T cells.
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.
authors: John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia.
authors: John A
authors: JA
authors: Altin
authors: Stephen R
authors: SR
authors: Daley
authors: Jason
authors: J
authors: Howitt
authors: Helen J
authors: HJ
authors: Rickards
authors: Alison K
authors: AK
authors: Batkin
authors: Keisuke
authors: K
authors: Horikawa
authors: Simon J
authors: SJ
authors: Prasad
authors: Keats A
authors: KA
authors: Nelms
authors: Sharad
authors: S
authors: Kumar
authors: Lawren C
authors: LC
authors: Wu
authors: Seong-Seng
authors: SS
authors: Tan
authors: Matthew C
authors: MC
authors: Cook
authors: Christopher C
authors: CC
authors: Goodnow
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002352:Carrier Proteins / Q000502:physiology*; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D002352:Carrier Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C499188:Ndfip1 protein, mouse
keywords: Aire (Autoimmune Regulator); Interleukin-4; T lymphocyte; allergy; immunological tolerance