title: Sub-optimal CD4+ T-cell activation triggers autonomous TGF-β-dependent conversion to Foxp3+ regulatory T cells.
abstract: Classical in vitro Treg conversion assays, which rely on optimal T-cell activation in the presence of exogenous TGF-β, induce Foxp3 expression at a frequency far above that which is observed in vivo in Treg-dependent models of oral or transplantation tolerance. We have found that suboptimal murine T-cell activation in vitro results in induction of Foxp3 expression, in the absence of exogenous TGF-β, at a frequency similar to that which we found in vivo upon anti-CD4-induced transplantation tolerance. We show that TCR triggering with either low-dose anti-CD3 or low-dose agonist peptide, as well as down-modulation of the TCR signal with non-depleting anti-CD4, promotes TGF-β production by T cells, an event that precedes Foxp3 expression and is Foxp3 independent. These findings support the view that sub-immunogenic regimens lead to dominant tolerance as a result of T-cell intrinsic properties.
authors.affiliation: Instituto de Medicina Molecular, Medical School of University of Lisbon, Lisbon, Portugal.
authors.forename: Vanessa G
authors.initials: VG
authors.lastname: Oliveira
authors.forename: Marta
authors.initials: M
authors.lastname: Caridade
authors.forename: Ricardo S
authors.initials: RS
authors.lastname: Paiva
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Demengeot
authors.forename: Luis
authors.initials: L
authors.lastname: Graca
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing; D017252:CD3 Complex / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D017252:CD3 Complex; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta