Self/nonselfPub Date : 2010-01-01DOI: 10.4161/self.1.1.10962
Travis J Crites, Rajat Varma
{"title":"On the issue of peptide recognition in T cell development.","authors":"Travis J Crites, Rajat Varma","doi":"10.4161/self.1.1.10962","DOIUrl":"10.4161/self.1.1.10962","url":null,"abstract":"<p><p>CD4-CD8 double positive (DP) thymocytes undergo a differentiation process in the thymus where they are selected based on their ability to recognize peptide antigens presented on self major histocompatibility complex (MHC) molecules. The first stage of this process is positive selection, a quality-control mechanism which ensures that the T cell receptors (TCR) presented on developing thymocytes can transmit signals via peptides presented on either MHC class I (MHC1) or MHC class II (MHC2) molecules. Work over the past decade has revealed that the peptides that drive positive selection of both CD4 and CD8 lineage cells deliver only weak TCR signals. In line with these observations, specialized protein degradation machineries have been discovered in the thymic cortex that presumably generate specialized low-affinity peptide repertoires for presentation on MHC1 and MHC2 molecules. TCR signals transduced through these weak-affinity ligands in the early stages of positive selection alter the kinetics of expression of CD4 and CD8 molecules and play a crucial role in commitment of thymocytes to either the CD4 or CD8 lineages. In this work, we review the experiments that explore the peptide repertoires that are presented to developing thymocytes during positive selection, the observed signaling patterns that lead to CD4 versus CD8 lineage commitment, and speculate about how specialized organization of the signaling machinery in DP thymocytes may allow for efficient transduction of weak signals during the course of positive selection.</p>","PeriodicalId":89270,"journal":{"name":"Self/nonself","volume":"1 1","pages":"55-61"},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091603/pdf/self0101_0055.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29872365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Self/nonselfPub Date : 2010-01-01DOI: 10.4161/self.1.2.11672
Norah L Smith, Stephanie Hammond, Deepti Gadi, Alice Wagenknecht-Wiesner, Barbara Baird, David Holowka
{"title":"Sphingosine derivatives inhibit cell signaling by electrostatically neutralizing polyphosphoinositides at the plasma membrane.","authors":"Norah L Smith, Stephanie Hammond, Deepti Gadi, Alice Wagenknecht-Wiesner, Barbara Baird, David Holowka","doi":"10.4161/self.1.2.11672","DOIUrl":"https://doi.org/10.4161/self.1.2.11672","url":null,"abstract":"<p><p>Mast cell stimulation via IgE receptors causes activation of multiple processes, including Ca(2+) mobilization, granule exocytosis, and outward trafficking of recycling endosomes to the plasma membrane. We used fluorescein-conjugated cholera toxin B (FITC-CTxB) to label GM(1) in recycling endsomes and to monitor antigen-stimulated trafficking to the plasma membrane in both fluorimeter and imaging-based assays. We find that the sphingosine derivatives D-sphingosine and N,N'-dimethylsphingosine effectively inhibit this outward trafficking response, whereas a quarternary ammonium derivative, N,N',N″-trimethylsphingosine, does not inhibit. This pattern of inhibition is also found for Ca(2+) mobilization and secretory lysosomal exocytosis, indicating a general effect on Ca(2+)-dependent signaling processes. This inhibition correlates with the capacity of sphingosine derivatives to flip to the inner leaflet of the plasma membrane that is manifested as changes in plasma membrane-associated FITC-CTxB fluorescence and cytoplasmic pH. Using a fluorescently labeled MARCKS effector domain to monitor plasma membrane-associated polyphosphoinositides, we find that these sphingosine derivatives displace the electrostatic binding of this MARCKS effector domain to the plasma membrane in parallel with their capacity to inhibit Ca(2+)-dependent signaling. Our results support roles for plasma membrane polyphosphoinositides in Ca(2+) signaling and stimulated exocytosis, and they illuminate a mechanism by which D-sphingosine regulates signaling responses in mammalian cells.</p>","PeriodicalId":89270,"journal":{"name":"Self/nonself","volume":"1 2","pages":"133-143"},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4161/self.1.2.11672","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29757644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}