As IL-23 inhibition exhibits long-lasting therapeutic efficacy way beyond the half-life of the biologics used (91), one might speculate that additional effects beyond the postulated upstream inhibition of IL-17A production might be clinically relevant. autoantigens were finally identified, suggesting that at least a subgroup of patients should be classified as suffering from a true autoimmune rather than autoinflammatory condition. Identification of resident memory T-lymphocytes (TRM) helped to understand why certain diseases relapse at the same site after seemingly effective therapy. Therefore, the in-depth characterization of autoreactive T-lyphocytes goes way beyond an academic exercise and opens the door toward improved therapies yielding durable responses. TRM are particularly suitable targets in this regard, and the clinical efficacy of some established and emerging therapeutic strategies such as the inhibition of Janus Kinase 3 or interleukin 15 may rely on their capacity to prevent TRM differentiation and maintenance. Research in this field brings us closer to the ultimate goal in the management of autoimmunity at large, namely resetting the immune system in order Cefmenoxime hydrochloride to restore the state of tolerance. induced Tregs (5). These subsets show functional and phenotypic similarities, but differ epigenetically. Tregs interact directly with different cell types of the innate and adaptive immune systems, but also exhibit their anti-inflamamtory effects via cytokines such as IL-10, IL-35, TGF-, and galectin-1. The frequency of autoreactive T-cells specific for a given self-antigen has been evaluated by peptide-MHC tetramer technology to be similar to those specific for foreign antigens, in the order of 1 to 10 per million T-cells (6). The study of the total autoreactive T-cell repertoire in healthy individuals is, however, hampered by the fact that peripheral tolerance mechanisms make autoreactive T-cells functionally indistinguishable. Richards and colleagues addressed this issue by analyzing the exposed self-reactive T-cells upon removal of Treg cells in Foxp3DTR mice. Self-reactivity was observed in about 4% of peripheral CD4+ and Mouse monoclonal to STAT3 CD8+ T-cells, a frequency similar to the responses to allo-MHC complexes or superantigens (7). Thus, autoreactive T-cells Cefmenoxime hydrochloride are readily detectable in healthy individuals, but they are efficiently controlled by peripheral tolerance. When the tolerance is broken, autoreactive T-cells may become activated and generate overt autoimmunity. In that regard, interesting insights are being generated by the therapeutical use of checkpoint inhibitors, e.g., CTLA-4 and programmed cell death protein 1 (PD-1) blocking antibodies. These compounds represent a promising approach to treat various cancers since they boost specific anti-tumor T-cell immunity by restraining tolerogenic mechanisms exploited by the tumor. The drawback is that peripheral tolerance is weakened and patients may develop so called immune-related adverse events (irAEs). These irAEs differ from classic organ-specific Cefmenoxime hydrochloride autoimmune disease in as much as they affect a broader range of organs and cells (8). These data clearly show how autoreactive T-cells may be reactivated in particular situations. How tolerance is broken or evaded during classical autoimmunity is a complex and incompletely understood matter. Autoimmune responses are currently thought to arise from a combination of genetic and environmental factors. For example, HLA polymorphisms could result in altered regulation or reduced threshold for autoreactive T-cells, with environmental factors constituting the initial triggering for inappropriate activation (9). Regarding peripheral tolerance, Tregs may become dysfunctional through at least 4 distinct mechanisms, namely plasticity (capacity to produce IL-17 after loss of the transcription factor FOXP3), reduced CD18 expression, epigenetic changes, and inhibitory mRNA targeting FOXP3. This allows proinflammatory cells such as Th1 and TH17 lymphocytes to escape regulation and to perform their effector functions in an uncontrolled manner (10). Activation of autoreactive T-lymphocytes is a key event in almost any kind of autoimmune response: while T-cells are important effectors in some entities (e.g., psoriasis), their principal mode of action in other diseases is to provide help for B-lymphocytes produce the disease-mediating auto-antibodies (e.g., bullous pemphigoid). A clinical consequence is that drugs targeting T-cell function are highly effective to treat the former, while B-cell directed drugs currently represent the gold standard for the latter. We will now discuss the.