| Summary: | <p>Induced regulatory T cells (iTreg) play an important role in the induction of tolerance to self and non-self antigens. Harnessing their suppressive potential has therapeutic implications for the treatment of autoimmune conditions and transplant rejection. Although the role of TGFβ-conditioned iTreg in natural and therapeutic tolerance is indisputable, their mechanism of action as well as factors that influence their function and stability <em>in vivo</em> remain unclear. Here it is shown that TGFβ-conditioning of T cells in the absence of any Foxp3 expression is insufficient for conferring a suppressive phenotype <em>in vivo</em>, whilst Foxp3 expression is sufficient to enable naïve T cells to become suppressive both <em>in vitro</em> and <em>in vivo</em>. Graft antigen was found to enhance the number of iTreg-derived Foxp3+ cells localising to the draining lymph nodes of recipients, and this was associated with histone modifications at the Foxp3 locus that suggested a stabilisation or 'affirmation' of Foxp3 expression. Finally, iTreg were shown to 'out-compete' naïve T cells in forming clusters with dendritic cells. Activated inflammatory T cells could also 'out-compete' naïve T cells. However, unlike activated T cells, iTreg did not activate interacting DCs to the same extent, and this may potentially be a mechanism of their action <em>in vivo</em>.</p>
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