mTECs play a privileged function within this pivotal procedure by their particular capacity expressing a broad selection of peripheral self-antigens that are presented to developing T cells. control the structure and complicated three-dimensional organization from the thymic medulla. research are indicated within this amount. Tissue-restricted self-antigens (TRAs) portrayed and provided by mTECs can result in the deletion of autoreactive T cells as well as the induction of nTregs. These self-antigens may also be used in and provided by citizen cDCs, resulting in T-cell deletion and the induction of nTregs. Furthermore, migratory cDCs and pDCs also reinforce the establishment of central T-cell tolerance via the presentation of antigens captured in the periphery. Migratory cDCs are also involved in T-cell deletion and the induction of nTregs, whereas pDCs only contribute to the deletion of autoreactive T cells in mice. Thymic B cells have also been shown to participate in the deletion of autoreactive T cells and the generation VHL of nTregs. mTECs act as APCs Medullary thymic epithelial cells have thus been in the beginning recognized to play a privileged role in T-cell tolerance because they constitute an antigen reservoir that mirrors the peripheral self (33). However, the use of transgenic mouse models that mimic TRA expression in the thymus have shown that mTECs can efficiently induce the clonal deletion of CD8+ T cells (42, 54). Recent studies have exhibited that they also act as APCs to CD4+ T cells. mTECs have the ability to autonomously present endogenously expressed TRAs via MHCII molecules by using an unconventional endogenous pathway called macroautophagy, which allows the shuttling of cytoplasmic constituents into lysosomes (55, 56). Aire+ mTECs can induce both the unfavorable selection of autoreactive T cells as well as the generation of nTreg cells (Physique ?(Physique2)2) (53, 57C60). The induction of nTreg cells was found to be mTEC-dependent because mTECs have the ability to foster the development of Foxp3?CD25+ nTreg precursors (61). In accordance with these findings, mice showing an enhanced mTEC compartment display increased production of nTreg cells (62, 63). Conversely, mice showing a reduced mTEC compartment exhibit a reduction of nTreg cells (64, 65). Interestingly, a recent study has shown that a large proportion of thymic Tregs corresponds to peripheral recirculating Tregs (66). The participation of mTECs to this phenomenon of recirculation to the thymus remains to be examined. Interestingly, post-Aire mTECs were found to maintain intermediate TRA expression (24). Thus, it is plausible that this newly recognized mTEC subset plays a role in the establishment of T-cell tolerance. Further studies, based for instance on cell-specific ablation, are needed to address this issue. Moreover, although MHCII?/loCD80?/loAire? and MHCIIhiCD80hiAire? mTECs express fewer genes compared with Aire+ mTECs (34), only a few thousands Naftopidil (Flivas) genes are differentially expressed, which suggests that these immature subsets could have a non-redundant function in the induction of T-cell tolerance. In addition, these unique mTEC subsets express different levels of MHCII and costimulatory molecules, which may significantly impact T-cell selection. Consistent with these observations, knock-down of MHCII molecules specifically in Aire+ mTECs prospects to an increased proportion of CD4+ SP and an enhanced selection of nTregs (59). These findings suggest that there is an underlying division of labor within mTEC subsets, with immature mTECs likely Naftopidil (Flivas) providing more potent induction of nTregs and mature mTECs preferentially prone to unfavorable selection. Of notice, the dynamics of the interactions of CD8+ and CD4+ T cells with mTECs remain unknown to date. It would be very useful to compare the interactions of medullary CD8+ and CD4+ T cells with Aire? and Aire+ mTECs to determine to what extent the frequency and duration of these interactions influence T-cell outcomes. Two-photon imaging experiments assessing new thymic slices are expected to achieve this goal in the near future and may reveal a complex choreography between SP thymocytes and mTECs. Migratory DCs reinforce the presentation of self-antigens Although mTECs express a diverse repertoire of TRAs that largely contribute to the induction of T-cell tolerance, they cannot encompass the spectrum of all peripheral Naftopidil (Flivas) self-antigens. Migratory DCs have been shown to reinforce the deletion of autoreactive thymocytes by sampling peripheral self-antigens that would otherwise be undetectable to developing thymocytes. Studies based on Rag2?/? OTII TCR-transgenic mice have shown that migratory cDCs induce the unfavorable selection of autoreactive CD4+ thymocytes (12, 67). Interestingly, in co-culture assays, Sirp+ cDCs efficiently convert CD4+CD25? thymocytes into CD4+CD25+Foxp3+ nTregs (12, 68). Migratory cDCs were also found to efficiently induce nTreg cells (12). Thus, in the constant state, migratory cDCs have the ability to transport antigens captured in the periphery and.