title: An alternative role for Foxp3 as an effector T cell regulator controlled through CD40.
abstract: The BDC2.5 T cell clone is highly diabetogenic, but the transgenic mouse generated from that clone is surprisingly slow in diabetes development. Although defining pathogenic effector T cells in autoimmunity has been inconsistent, CD4(+) cells expressing the CD40 receptor (Th40 cells) are highly diabetogenic in NOD mice, and NOD.BDC2.5.TCR.Tg mice possess large numbers of these cells. Given the importance of CD40 for pathogenic T cell development, BDC2.5.CD40(-/-) mice were created. Regulatory T cells, CD4(+)CD25(hi)Foxp3(+), develop normally, but pathogenic effector cells are severely reduced in number. Th40 cells from diabetic BDC2.5 mice rapidly induce diabetes in NOD.scid recipients, but Th40 cells from prediabetic mice transfer diabetes very slowly. Demonstrating an important paradigm shift, effector Th40 cells from prediabetic mice are Foxp3(+). As mice age, moving to type 1 diabetes development, Th40 cells lose Foxp3. When Th40 cells that are Foxp3(+) are transferred to NOD.scid recipients, disease is delayed. Th40 cells that are Foxp3(-) rapidly transfer disease. Th40 cells from BDC2.5.CD40(-/-) mice do not transfer disease nor do they lose Foxp3 expression. Mechanistically, Foxp3(+) cells produce IL-17 but do not produce IFN-γ, whereas Foxp3(-) Th40 cells produce IFN-γ and IL-2. This poses a new consideration for the function of Foxp3, as directly impacting effector T cell function.
authors.affiliation: Webb-Waring Center, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Gisela M
authors.initials: GM
authors.lastname: Vaitaitis
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Carter
authors.forename: Dan M
authors.initials: DM
authors.lastname: Waid
authors.forename: Michael H
authors.initials: MH
authors.lastname: Olmstead
authors.forename: David H
authors.initials: DH
authors.lastname: Wagner
mesh_terms: D000818:Animals; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D011236:Prediabetic State / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma