Effector Tregs: middle-men in TGFβ activation

Regulatory T-cells (Tregs) are an inherent suppressive cell of the immune system with an established developmental requirement for the cytokine transforming growth factor β (TGFβ). However, the precise mechanisms by which mature Tregs utilize TGFβ during disease are unclear. In the May issue of Immunity, we have demonstrated that effector regulatory T-cells are essential activators of latent-TGFβ which is crucial to suppress ongoing inflammation. A failure to regulate effective immunity results in chronic inflammation which can lead to immunopathology and carcinogenesis. One of the key molecules involved in immune cell suppression is the cytokine TGFβ, which crucially must be activated from its latent state in order to function [1]. An essential function of TGFβ is to drive the development of Tregs, both naturally derived thymic Tregs and the peripherally induced Tregs that are converted from the naïve T-cell population (pTregs) [2]. This critical subset of T-cells with an inherent suppressive role has been a huge focus of research both mechanistically and therapeutically, with current treatments for autoimmunity and transplantation involving the ex vivo expansion of patient's Tregs and conversely selective Treg depletion during cancer treatment. Several in vivo studies have clearly shown that, in addition to its role in Treg development, TGFβ plays a fundamental role in the suppressive function of Tregs. However, the precise mechanisms by which TGFβ mediates Treg biology are unclear, with conflicting reports existing within the literature, most notably in studies utilizing T-cell transfer colitis. Within this colitis model, Tregs are essential for the suppression of disease but are still able to suppress inflammation when they lack the ability to produce TGFβ [3, 4]. However, the use of blocking antibodies in the same study demonstrates the complete dependence on TGFβ for disease suppression [3]. Furthermore, effector T-cells themselves must respond to TGFβ for Treg-mediated prevention of colitis, as T-cells require functional TGFβ receptors to be supressed [3]. Collectively, these data indicate that TGFβ is absolutely required for Tregs to suppress effector T-cells, but Tregs themselves do not need to be the source of TGFβ. is the regulation of latent TGFβ during intestinal inflammation. The TGFβ1 gene (TGFβ1 being the predominate isoform produced by the immune system) encodes latency associated peptide (LAP), which after transcription remains non-covalently bound preventing the active TGFβ dimer engaging its receptor. This so called LAP " straight-jacket " that surrounds the TGFβ dimer contains an RGD motif which can be bound by …