In contrast, DC2 are generally less efficient at induction of pTreg cells and tolerance, although some DC2 could also induce pTreg cells in the intestines and expand the existing tTreg cells as well as promote other forms of Treg cell-independent tolerance [84C86]. of T cells to prevent overt anti-self reactions [2, 3]. However, it is obvious the adult repertoire still consists of T cells having a degree of reactivity to self [4]. This self-reactivity is definitely explained by several factors, such as insufficient thymic deletion in case of some tissue restricted antigens (TRAs), which are offered to T cells in the thymus less efficiently (in comparison to their demonstration by specialized antigen showing cells (APCs) in the peripheral immune system) [5]. More broadly, it is obvious that T cell receptors (TCR) are cross-reactive to some degree, that is, they recognize multiple, sometimes even unrelated, peptides (molecular mimics) offered by major histocompatibility complex (MHC) molecules [6, 7]. Although the specific match, or affinity, between cross-reactive peptides and specific TCRs may differ Nilotinib (AMN-107) significantly, such Fgfr1 cross-reactivity increases the risk of some peripheral T cells remaining reactive against self-antigens [8C11]. A risk of autoimmunity is definitely further improved because, especially during infections, some self-reactive peripheral T cells can be primed actually by low-affinity peptides that are below their unique thresholds for bad selection [5, 10C12]. Additionally, a degree of self-reactivity correlates with increased TCR signaling during thymic selection and improved expression of CD5; these CD5hi cells can be self-reactive but nevertheless survive thymic selection and therefore may also present higher risks of autoimmune reactions [3, 13, 14]. Therefore, additional mechanisms of tolerance are necessary to prevent autoimmune activation of peripheral self-reactive T cells. Functions of Treg cells are indispensable to maintain immune homeostasis, and the absence of Treg cells prospects to overt auto-aggressive activation of the immune system [15]. However, thymically-produced tTreg cells may be overwhelmed by specific pro-inflammatory autoimmune activation; also, in some individuals, the development of self-antigen specific tTreg cells may be compromised [5, 10, 11, 16]. Similarly, in various animal models of autoimmune diseases, the autoimmune process can be initiated in Nilotinib (AMN-107) healthy animals after immunization with specific self-antigens either in the presence of adjuvants or in the context of an launched infectious agent, ultimately leading to the priming of the pre-existing self-reactive T cells [11, 17]. Overall, self-reactive T cells continue to persist in the peripheral immune system, and, for multiple reasons, thymically-imposed mechanisms of tolerance may fail to prevent a specific immune priming of such self-reactive T cells, ultimately leading to the autoimmune process [5, 10, 11, 17, 18]. Crucially, specific mechanisms of tolerance originating in the peripheral immune system can further prevent activation of self-reactive T cells that escaped thymic deletion or failed to be inhibited by the functions Nilotinib (AMN-107) of tTreg cells [19]. In a process analogous to its functions in medullary thymic epithelial cells (mTEC), the Autoimmune Regulator (AIRE) mediates expression of TRAs in peripheral non-hematopoietic stromal cells and induces deletion of self-reactive T cells [20]. However, antigens derived from apoptotic cells represent a critical, and arguably more abundant source of tissue self-antigens, and their presentation to both CD4+ and CD8+ Nilotinib (AMN-107) T cells relies on the functions of DCs [21C25]. Although cross-presented antigens acquired from numerous tissues may lead to deletion of CD8+ T cells, the tolerance spontaneously induced by DCs in this way may be particularly important for the maintenance of immune homeostasis to self- and oral antigens within the intestine [25C29]. In contrast, the spontaneous induction of mechanisms of peripheral tolerance including CD4+ T cell deletion, anergy and conversion of peripheral (p)Treg cells in response to antigens from organs that are more insulated from your immune system (such as the central nervous system (CNS)), may be less efficient [17]. Therefore, spontaneously induced peripheral tolerance induced by DCs may not prevent autoimmune responses against the CNS and other organs whose antigens are not sufficiently available for the specific induction of mechanisms of peripheral tolerance. However, such tolerogenic functions of DCs can be unmasked and enabled.