However, not all anergic T cells can become pTreg cells, and the specific mechanisms governing the fates of T cells responding to tolerogenic DCs remain unclear

However, not all anergic T cells can become pTreg cells, and the specific mechanisms governing the fates of T cells responding to tolerogenic DCs remain unclear. with a production of thymically derived regulatory T (tTreg) cells, all shape the T cell receptor (TCR) repertoires Onalespib (AT13387) and responsiveness of T cells to prevent overt anti-self responses [2, 3]. However, it is clear that the mature repertoire still contains T cells with a degree of reactivity to self [4]. This self-reactivity is explained by several factors, ANPEP such as insufficient thymic deletion in case of some tissue restricted antigens (TRAs), which are presented to T cells in the thymus less efficiently (in comparison to their presentation by specialized antigen presenting cells (APCs) in the peripheral immune system) [5]. More broadly, it is clear that T cell receptors (TCR) are cross-reactive to some degree, that is, they recognize multiple, sometimes even unrelated, Onalespib (AT13387) peptides (molecular mimics) presented by major histocompatibility complex (MHC) molecules [6, 7]. Although the specific fit, or affinity, between cross-reactive peptides and specific TCRs may differ significantly, such cross-reactivity increases the risk of some peripheral T cells remaining reactive against self-antigens [8C11]. A risk of autoimmunity is further increased because, especially during infections, some self-reactive peripheral T cells can be primed even by low-affinity peptides that are below their original thresholds for negative selection [5, 10C12]. Additionally, a degree of self-reactivity correlates with increased TCR signaling during thymic selection and increased expression of CD5; these CD5hi cells can be self-reactive but nevertheless survive thymic selection and therefore may also present greater risks of autoimmune responses [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 leads 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 healthy animals after immunization with specific self-antigens either in the presence of adjuvants or in the context of an introduced 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 Onalespib (AT13387) 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 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+ T cells relies on the functions of DCs [21C25]. Although cross-presented antigens acquired from various 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 the immune system (such as the central nervous system (CNS)), may be less efficient [17]. Therefore, spontaneously induced peripheral Onalespib (AT13387) 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 Onalespib (AT13387) peripheral tolerance. However, such tolerogenic functions of DCs can be unmasked and enabled by a targeted delivery of various tissue-specific antigens, allowing for their efficient presentation to self-reactive T cells [30C32]. Establishing the roles of DCs as key inducers of peripheral tolerance Initially, DCs were considered to be unlikely candidates for tolerance induction. Since their early discovery by Ralph Steinman, DCs.

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