In this review we have highlighted the role of LNSCs in the regulation of CD8+ T cell immune responses in peripheral lymph nodes, thereby adding another layer of protection, in addition to the role of resting DCs, against autoimmunity. LNSCs have recently been implicated in the induction of peripheral CD8+ T cell tolerance due to their ability to endogenously express, process, and present PTAs. Furthermore, LNSCs express surface molecules, such as MHC class II and PD-L1, similar to those expressed by mTECs in the thymus and APCs. For future studies it will be important to address some of the new questions that have emerged with respect to the biology and function of LNSCs. Further work will help us to (1) dissect the specific roles that DCs and LNSCs have in the induction and maintenance of tolerance to intestinal antigens, (2) gain a more in-depth understanding of the molecular mechanisms underlying self-tolerance induction by LNSCs and the impact of inflammation on this function, (3) evaluate the relationship of LNSCs to the FRN, and (4) determine if the APC function of LNSCs extends to the acquisition and presentation of exogenous antigens. Finally, it is important to mention that so far the studies done on LNSCs have focused on their role in CD8+ T cell tolerance. At the moment, we do not know if presentation of PTAs by LNSCs can also induce tolerance of CD4+ T cells. Based on the finding that LNSCs express MHC class II (I-A(b)) molecules it is possible that they may present self-antigens to CD4+ T cells and induce tolerance. However, this has yet to be elucidated.