During aging, homeostatic proliferation declines to a certain extent but is retained over extensive periods of time [84]

During aging, homeostatic proliferation declines to a certain extent but is retained over extensive periods of time [84]. incapable of recognizing pMHC antigen and the others not discriminating between self and non-self-antigens. Therefore, in order to produce a pool of T cells capable of recognizing foreign antigen, but at the same time not eliciting autoimmune disease, non-functional and autoreactive cells must be removed from the T cell pool. These processes are termed positive and negative selection, respectively, and are both controlled by signaling Fmoc-Lys(Me3)-OH chloride through the TCR. Accordingly, rather than mediating digital on/off signals, in thymocytes the TCR has to integrate signals inducing multiple possible fates: T cells that do not possess a detectable affinity to pMHC die by neglect, those that have low to intermediate affinity to pMHC are positively selected and the fraction of cells that bind pMHC with high affinity is usually deleted or driven into a pathway called agonist selection to clonally divert thymocytes into unconventional T cell lineages (Physique 1) (for review see [1,2]). Open in a separate window Physique 1 Conventional and agonist selected T cells possess different affinity windows for positive selection. Conventional T cells require low to moderate TCR affinities to peptide: MHC to receive survival signals, whereas agonist selected T cells depend on relatively high affinities towards peptide: MHC to be positively selected. The TCR consists of a disulfide bridge linked TCR or TCR dimer, complexed with CD3, CD3, CD3, and the chain. Signaling is initiated by phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) within the TCR:CD3 complex by the Src family kinase Lck. Phosphorylation of ITAMs results in recruitment of the kinase ZAP-70, which in turn results in the formation of adaptor scaffolds and the activation of multiple downstream signaling pathways including Ca2+ signaling, MAP kinases, such as Erk, PI3K/Akt signaling, as well as NF-B. Given the central role of phosphorylation, in particular during proximal TCR signaling, it is unsurprising that phosphatases play a critical regulatory role (for review see [3]). Notably, phosphatases may act as positive or unfavorable regulators of the TCR signals by removing inhibitory or activating phosphates, respectively. The receptor protein tyrosine phosphatase CD45 constitutes a key positive regulator as it dephosphorylates inhibitory phospho-tyrosines of Lck. However, it may also act as a negative regulator through dephosphorylation of CD3, suggesting that it contributes to tuning of TCR signals in response to antigen [4]. Calcineurin, in response to increased Ca2+ levels, dephosphorylates, and thereby induces nuclear translocation of NFAT transcription factors [5]. Conversely, Ptpn22 and SHP-1 (Ptpn6) constitute crucial unfavorable regulators [6]. In particular, SHP-1 has been implicated as a central component of a negative feedback loop allowing for pMHC-specific T cell activation at low ligand concentrations in the presence of Fmoc-Lys(Me3)-OH chloride an excess of low-affinity ligands [7,8]. In this model, SHP-1 forms a critical rheostat for a digital on/off response at the level of Erk phosphorylation. Another Fmoc-Lys(Me3)-OH chloride group of phosphatases linked to Erk activation are dual-specificity phosphatases (DUSPs) capable of dephosphorylating MAP kinases at both serine/threonine and tyrosine residues [9]. Quantitative as well as qualitative differences elicited by positively and negatively selecting pMHC ligands have been described. Clonal deletion is usually induced rapidly within a few hours Fmoc-Lys(Me3)-OH chloride after signaling [10]. Consistently, in an inducible model of ZAP-70 activation, ZAP-70 activity of 1 1 h was sufficient to induce unfavorable selection [11]. Conversely, sustained ZAP-70 activity FRP of at least 36 h was required to promote positive selection [11]. Similarly, sustained activity of Erk is required for positive selection, whereas Erk activity rapidly wanes after induction of unfavorable selection [12,13,14]. Moreover, whereas negatively selecting pMHC ligands restrict Erk signaling to the plasma membrane, positively selecting ligands induce distribution of the Erk signaling module throughout the cytoplasm [15]. The role of phosphatases during thymic selection has not been comprehensively characterized. DUSP5 and DUSP6 (also termed MKP-3) have been implicated in positive selection. Thus, transgenic expression of.

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