Bench, Bedside, Toolbox: T-Cells Deliver on Every Level

Decades of research have shed light on many aspects of T-cells, spawning a myriad of diagnostic and therapeutic applications in the process. Chief among those properties is the unique ability of T-cells to scan the intra-cellular protein content to detect anomalies in tissues, be it the presence of pathogens or cellular transformation. The tri-partite interaction between the T-cell receptor (TCR), its co-receptor CD4 or CD8, and peptide-major histocompatibility (pMHC) ligands determines the outcome of an encounter between a T-cell and an antigen presenting cell and can result in ignorance or trigger a cellular activation program central to adaptive immunity. Over the years, tremendous insights into the rules that govern this interaction have been gained at the molecular and cellular levels, resulting in the development of technologies and tools that improve our understanding of the dynamics of antigen-specific T-cell responses in vivo as well as therapeutic modalities aimed at harnessing the power of T-cells through vaccines, cellular therapies, and biologics. The selection of 18 articles that constitute this Research Topic reflects these advances in many ways and provides a snapshot of the current focus in the field, with an emphasis on the efforts made in order to translate our knowledge of T-cell biology into tools for therapy, diagnosis, and immune-monitoring. From a fundamental point of view two primary research articles examine how T-cells discriminate between pMHC antigens and integrate signals that result in different cellular outcomes. Schaft et al. tested a panel of altered peptide ligands of human glycoprotein (gp)100 and identified a partial agonist that dissociates signaling networks downstream of TCR triggering (1). The altered peptide ligand they identified elicits cytotoxicity but negligible or no cytokine secretion nor NFAT-mediated transcription, an intriguing observation that appears related to the extent of binding by TCR and CD8a and reveals the intricacies of signal transduction downstream of the TCR. In an extensive study of T-cell activation, van den Berg et al. examined the response of a human CD8 C T-cell clone against several agonists of different affinities for the TCR (2). Their results support a model of epitope discrimination at the cellular level based on the integration of TCR signals, whereby the sum of signals read by a T-cell determines the functional response, rather than by the individual properties of receptor‐ligand interactions. These two reports further highlight the analog nature of signal processing in T-cells, which enables diverse functional outcomes based on the concatenation of input signals rather than a binary response mediated via a simple on/off switch mechanism.