We all have been taught that the immune system is educated in the thymus; however, where the im-mune system receives the second lesson in order to be tolerant against non-harmful pathogens, such as commensal bacteria, has never been addressed. Considering that com-mensal bacteria colonize the intestine and that regulatory T (Treg) cells are enriched in this organ, one could think that the intestine is the place where this second lesson would occur. This idea was now sustained by the work of Lathrop et al., which sheds new light on the complex mechanism of peripheral tolerance induction. The immune system has to respond selectively to harmful non-self patho-gens and at the same time needs to minimize reactions against self and non-harmful antigens. This highly fine-tuned mechanism is possible due to a strict selection process, which happens in the thymus. Potentially autoreactive T cell progenitors, which recognize self antigens with their T cell receptor (TCR), are either deleted or converted into thymic-derived regulatory T cells (tTreg). This process, called central tolerance, is essential for the education of T cells to respond selectively against foreign antigens. However, this thymic control is not sufficient. Therefore, the immune system avails itself of several other mechanisms, which take place in the periphery (peripheral tolerance), to control potentially autoreactive T cells, which escaped the checkpoint of central tolerance. Among these mechanisms, the action of regulatory T (Treg) cells, which can be either selected in the thy-mus (tTreg) or induced in the periphery (iTreg), is one of the most studied. Treg cells are essential to control autoreactive T cells, which can react to self antigens and cause damage to the host. The key role of Treg cells in the peripheral im-mune response is evident in murine models [1] and in humans [2]. Scurfy mice [1] and IPEX (immunodysregula-tion polyendocrinopathy enteropathy X-linked syndrome) patients [2] lack the master transcription factor of Treg cells, Foxp3, and consequently develop strong autoimmune disorders. Importantly, a severe form of autoimmune enteropathy is characteristic for scurfy mice [1] and IPEX patients [2]. This underscores the importance of Treg cells for the control of the immune response against self antigens in the intestine. However, the intestine is not only a source of self anti-gens, but also contains a vast collection of non-self antigens, such as commensal bacteria, which can promote the activa-tion of naïve T cells that causes immune pathology such as inflammatory bowel disease (IBD). It is therefore crucial for the immune system to establish a second checkpoint where naïve T cells, which are potentially able to respond to non-self antigens, are re-educated to be tolerant. If the thymus is the "bank" of self antigens, we propose the intestine to be the "shopping mall" of non-self antigens. Interestingly, it was shown that naïve T cells can go to the intestine and upregulate Foxp3 (iTreg), thereby acquiring a regulatory function. However, an important piece of knowl-edge was still missing: are these iTreg cells generated against self or foreign antigens derived from the commensal bacteria? The study by Lathrop et al. [3] answered this question, showing that iTregs are indeed induced by TCR recognition of commensal antigens. In turn they suggest the intestine as the key organ for the induction of peripheral tolerance. First, Lathrop et al. [3] found that Treg cells and effector T cells in the intestine express very different TCRs from each other, which were in turn different again from the TCRs of T cells in other organs. These data suggested that the colonic T cell population is strongly shaped by the local antigens in the intestine. In fact the authors next demonstrate that many of these local antigens are derived from intestinal bacteria, which could be passed between mice. One caveat of these experiments was that tTreg cells, which had been selected in the thymus, could have been expanded in the intestine due to cross-reactivity to microbial antigens. However, the authors found that a substantial population of Treg cells