title: High TCR stimuli prevent induced regulatory T cell differentiation in a NF-κB-dependent manner.
abstract: The concentration of Ag or mitogenic stimuli is known to play an important role in controlling the differentiation of naive CD4(+) T cells into different effector phenotypes. In particular, whereas TCR engagement at low Ag doses in the presence of TGF-β and IL-2 can promote differentiation of Foxp3-expressing induced regulatory T cells (iTregs), high levels of Ag have been shown in vitro and in vivo to prevent Foxp3 upregulation. This tight control of iTreg differentiation dictated by Ag dose most likely determines the quality and duration of an immune response. However, the molecular mechanism by which this high-dose inhibition of Foxp3 induction occurs is not well understood. In this study, we demonstrate that when cells are in the presence of CD28 costimulation, TCR-dependent NF-κB signaling is essential for Foxp3 inhibition at high doses of TCR engagement in mouse T cells. Prevention of Foxp3 induction depends on the production of NF-κB-dependent cytokines by the T cells themselves. Moreover, T cells that fail to upregulate Foxp3 under iTreg-differentiating conditions and high TCR stimulation acquire the capacity to make TNF and IFN-γ, as well as IL-17 and IL-9. Thus, NF-κB helps T cells control their differentiation fate in a cell-intrinsic manner and prevents peripheral iTreg development under conditions of high Ag load that may require more vigorous effector T cell responses.
authors.affiliation: Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. lmoliner@medicine.bsd.uchicago.edu
authors.forename: Luciana L
authors.initials: LL
authors.lastname: Molinero
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Miller
authors.forename: César
authors.initials: C
authors.lastname: Evaristo
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: Alegre
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism; D010047:Ovalbumin / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D010455:Peptides / Q000276:immunology / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D016328:NF-kappa B; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D010047:Ovalbumin