Setting the threshold for extra-thymic differentiation of Foxp3+ Tregs: TGF-β-dependent and T-cell autonomous

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