title: The E3 ubiquitin ligase Itch is required for the differentiation of follicular helper T cells.
abstract: Follicular helper T cells (T(FH) cells) are responsible for effective B cell-mediated immunity, and Bcl-6 is a central factor for the differentiation of T(FH) cells. However, the molecular mechanisms that regulate the induction of T(FH) cells remain unclear. Here we found that the E3 ubiquitin ligase Itch was essential for the differentiation of T(FH) cells, germinal center responses and immunoglobulin G (IgG) responses to acute viral infection. Itch acted intrinsically in CD4(+) T cells at early stages of T(FH) cell development. Itch seemed to act upstream of Bcl-6 expression, as Bcl-6 expression was substantially impaired in Itch(-/-) cells, and the differentiation of Itch(-/-) T cells into T(FH) cells was restored by enforced expression of Bcl-6. Itch associated with the transcription factor Foxo1 and promoted its ubiquitination and degradation. The defective T(FH) differentiation of Itch(-/-) T cells was rectified by deletion of Foxo1. Thus, our results indicate that Itch acts as an essential positive regulator in the differentiation of T(FH) cells.
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Nengming
authors.initials: N
authors.lastname: Xiao
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Danelle
authors.initials: D
authors.lastname: Eto
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Elly
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Guiying
authors.initials: G
authors.lastname: Peng
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Yun-Cai
authors.initials: YC
authors.lastname: Liu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology; D018858:Germinal Center / Q000276:immunology; D007376:Interleukin-2 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000502:physiology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology*; D018418:Th2 Cells / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007376:Interleukin-2; D051560:Proto-Oncogene Proteins c-bcl-6; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases