title: Setting the threshold for extra-thymic differentiation of Foxp3+ Tregs: TGF-β-dependent and T-cell autonomous.
abstract: There is a lack of clarity regarding the conditions supporting de novo induction of Tregs. While there is widespread agreement in the literature over the need for optimal stimulation conditions and exogenous TGF-β in vitro, a number of studies indicate that sub-immunogenic conditions induce Tregs in vivo. These seemingly disparate findings have hindered the ability to pin down the conditions promoting Treg induction, including the role of co-stimulation and even the necessity for TGF-β. Two studies in this issue of the European Journal of Immunology re-examine these previous findings in detail and shed some light on the controversy. These studies demonstrate that Treg induction depends on reaching a certain threshold of signal strength: the requirement for co-stimulation is therefore not absolute but dictated by the strength of other signals received by the T cell. Furthermore, these studies demonstrate that the only source of TGF-β required for the induction of Tregs under sub-optimal condition is the T cells themselves. Overall, the picture that emerges is one where sub-immunogenicity, rather than a requirement for exogenous TGF-β, defines the conditions that support TGF-β-dependent Foxp3 induction in a T-cell autonomous fashion. The next challenge lies in utilizing this knowledge for the purpose of inducing Tregs for therapeutic gain.
authors.affiliation: Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Godkin
authors.forename: Awen
authors.initials: A
authors.lastname: Gallimore
mesh_terms: D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D018106:CD28 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta