T cell receptor engagement in the absence of proper accessory signals leads to T cell anergy. E3 ligases are involved in maintaining the anergic state. However, the specific molecules responsible for the induction of anergy have yet to be elucidated. Using microarray analysis we have identified here early growth response gene 2 (Egr-2) and Egr-3 as key negative regulators of T cell activation. Overexpression of Egr2 and Egr3 was associated with an increase in the E3 ubiquitin ligase Cbl-b and inhibition of T cell activation. Conversely, T cells from Egr3(-/-) mice had lower expression of Cbl-b and were resistant to in vivo peptide-induced tolerance. These data support the idea that Egr-2 and Egr-3 are involved in promoting a T cell receptor-induced negative regulatory genetic program.

Whether TCR engagement leads to activation or tolerance is determined by the concomitant delivery of multiple accessory signals, cytokines, and environmental cues. In this study, we demonstrate that the mammalian target of rapamycin (mTOR) integrates these signals and determines the outcome of TCR engagement with regard to activation or anergy. In vitro, Ag recognition in the setting of mTOR activation leads to full immune responses, whereas recognition in the setting of mTOR inhibition results in anergy. Full T cell activation is associated with an increase in the phosphorylation of the downstream mTOR target S6 kinase 1 at Thr421/Ser424 and an increase in the mTOR-dependent cell surface expression of transferrin receptor (CD71). Alternatively, the induction of anergy results in markedly less S6 kinase 1 Thr421/Ser424 phosphorylation and CD71 surface expression. Likewise, the reversal of anergy is associated not with proliferation, but rather the specific activation of mTOR. Importantly, T cells engineered to express a rapamycin-resistant mTOR construct are resistant to anergy induction caused by rapamycin. In vivo, mTOR inhibition promotes T cell anergy under conditions that would normally induce priming. Furthermore, by examining CD71 surface expression, we are able to distinguish and differentially isolate anergic and activated T cells in vivo. Overall, our data suggest that by integrating environmental cues, mTOR plays a central role in determining the outcome of Ag recognition.

Background Given the wealth of data in the literature on schizophrenia endophenotypes, it is useful to have one source to reference their frequency data. We reviewed the literature on disease-liability associated variants in structural and functional magnetic resonance images (MRI), sensory processing measures, neuromotor abilities, neuropsychological measures, and physical characteristics in schizophrenia patients (SCZ), their first-degree relatives (REL), and healthy controls (HC). The purpose of this review was to provide a summary of the existing data on the most extensively published endophenotypes for schizophrenia. Methods We searched PubMed and MedLine for all studies on schizophrenia endophenotypes comparing SCZ to HC and/or REL to HC groups. Percent abnormal values, generally defined as > 2 SD from the mean (in the direction of abnormality) and/or associated effect sizes (Cohen’s d) were calculated foreach study. Results Combined, the articles reported an average 39.4% (SD=20.7%; range=2.2-100%) of abnormal values in SCZ, 28.1% (SD=16.6%; range=1.6-67.0%) abnormal values in REL, and 10.2% (SD=6.7%; range=0.0-34.6%) in HC groups. Conclusions These findings are reviewed in the context of emerging hypotheses on schizophrenia endophenotypes, as well as a discussion of clustering trends among the various intermediate phenotypes. In addition, programs for future research are discussed, as instantiated in a few recent large-scale studies on multiple endophenotypes across patients, relatives, and healthy controls.