Differential calcium signaling and Kv1.3 trafficking to the immunological synapse in systemic lupus erythematosus
Stella A. NicolaouLisa NeumeierKoichi TakimotoSusan Molleran LeeHeather J. DuncanShashi KantAnne Barbara MongeyAlexandra H. FilipovichLaura Conforti
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Immunological synapse
Homeostasis
A bstract : T cell activation is based on interactions of T cell antigen receptors with MHC‐peptide complexes in a specialized cell‐cell junction between the T cell and antigen‐presenting cell—the immunological synapse. The immunological synapse coordinates naïve T cell activation and migration by stopping T cell migration with antigen‐presenting cells bearing appropriate major histocompatibility complex (MHC) peptide complexes. At the same time, the immunological synapse allows full T cell activation through sustained signaling over a period of several hours. The immunological synapse supports activation in the absence of continued T cell migration, which is required for T cell activation through serial encounters. Src and Syk family kinases are activated early in immunological synapse formation, but this signaling process returns to the basal level after 30 min; at the same time, the interactions between T cell receptors (TCRs) and MHC peptides are stabilized within the immunological synapse. The molecular pattern of the mature synapse in helper T cells is a self‐stabilized structure that is correlated with cytokine production and proliferation. I propose that this molecular pattern and its specific biochemical constituents are necessary to amplify signals from the partially desensitized TCR.
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Summary: T‐cell activation requires contact between T cells and antigen‐presenting cells (APCs) to bring T‐cell receptors (TCRs) and major histocompatibility complex peptide (MHCp) together to the same complex. These complexes rearrange to form a concentric circular structure, the immunological synapse (IS). After the discovery of the IS, dynamic imaging technologies have revealed the details of the IS and provided important insights for T‐cell activation. We have redefined a minimal unit of T‐cell activation, the ‘TCR microcluster’, which recognizes MHCp, triggers an assembly of assorted molecules downstream of the TCR, and induces effective signaling from TCRs. The relationship between TCR signaling and costimulatory signaling was analyzed in terms of the TCR microcluster. CD28, the most valuable costimulatory receptor, forms TCR–CD28 microclusters in cooperation with TCRs, associates with protein kinase C θ, and effectively induces initial T‐cell activation. After mature IS formation, CD28 microclusters accumulate at a particular subregion of the IS, where they continuously assemble with the kinases and not TCRs, and generate sustained T‐cell signaling. We propose here a ‘TCR–CD28 microcluster’ model in which TCR and costimulatory microclusters are spatiotemporally formed at the IS and exhibit fine‐tuning of T‐cell responses by assembling with specific players downstream of the TCR and CD28.
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Immunological synapse
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T cell receptor (TCR)-dependent regulatory T cell (Treg) activity controls effector T cell (Teff) function and is inhibited by the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Protein kinase C-theta (PKC-theta) recruitment to the immunological synapse is required for full Teff activation. In contrast, PKC-theta was sequestered away from the Treg immunological synapse. Furthermore, PKC-theta blockade enhanced Treg function, demonstrating PKC-theta inhibits Treg-mediated suppression. Inhibition of PKC-theta protected Treg from inactivation by TNF-alpha, restored activity of defective Treg from rheumatoid arthritis patients, and enhanced protection of mice from inflammatory colitis. Treg freed of PKC-theta-mediated inhibition can function in the presence of inflammatory cytokines and thus have therapeutic potential in control of inflammatory diseases.
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Antigen T cell receptors (TCR) recognize antigenic peptides displayed by the major histocompatibility complex (pMHC) and play a critical role in T cell activation. The levels of TCR complexes at the cell surface, where signaling is initiated, depend on the balance between TCR synthesis, recycling and degradation. Cell surface TCR interaction with pMHC leads to receptor clustering and formation of a tight T cell-APC contact, the immune synapse, from which the activated TCR is internalized. While TCR internalization from the immune synapse has been initially considered to arrest TCR signaling, recent evidence support the hypothesis that the internalized receptor continues to signal from specialized endosomes. Here, we review the molecular mechanisms of TCR endocytosis and recycling, both in steady state and after T cell activation. We then discuss the experimental evidence in favor of endosomal TCR signaling and its possible consequences on T cell activation.
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Abstract The mechanism by which a T cell utilizes its T-cell receptors (TCRs) to recognize foreign peptide major histocompatibility complexes (pMHCs) has not yet been fully deciphered. Much contention still exists surrounding TCR nanostructures before, during, and after synapse formation. Accurate measurements of single TCR location, diffusion/trafficking, clustering, and signaling at the live T-cell membrane have been hindered by the microscopy techniques available. Recently developed Lattice Light-Sheet Microscopy uses a structured light sheet to excite fluorescence in successive planes of a living T cell such that it can record 4D (x, y, z directions and time) images with exceptionally high temporal resolution (10ms/frame, ~1s/volume), finally allowing for precise single molecule tracking. Here we show that TCRs pre-exist in small microclusters prior to synapse formation in both naïve and stimulated resting CD4+ T cells. These clusters are very fast-moving, explaining the previous difficulties of tracking TCR motion and revealing a fast responding mechanism for antigen recognition. Upon encountering antigens, these smaller TCR nanoclusters traffic globally and quickly to the cell interface, aggregate into larger microclusters, and form the immunological synapse. Finally, we compare and contrast the receptor dynamics of CAR-T cells with those of naturally occurring T cell receptors. These findings precisely quantify TCR and CAR dynamics three-dimensionally, suggesting new mechanistic details of the speed and accuracy of TCR signaling and providing new information upon which to base future immunotherapies. Citation Format: Jillian N. Rosenberg, Guoshuai Cao, Fernanda Borja-Prieto, Yanran He, Hans Schreiber, Jun Huang. Direct real-time visualization and quantification of T cell receptor dynamics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 488.
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Abstract The cover image of this issue consists of a confocal microscopic FRET image showing immunological synapse formation in Jurkat T cells, and is taken from Roszik et al. ( pp . 1288–1297). In this article, the authors characterize TCR‐ζ, a heterodimer of TCR‐α and β chains each coupled to complete human CD3ζ, in gene‐engineered T cells and assess whether this receptor is able to interact with surface molecules and drive correct synapse formation in Jurkat T cells. The authors notably demonstrate that TCR‐ζ is able to induce synapse formation upon antigen recognition, and that synapse formation induced by TCR‐ζ is independent of TCR‐CD3.
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T lymphocyte activation by specific antigen requires prolonged TCR occupancy and sustained signaling. This is accomplished by the formation of a specialized signaling domain, the immunological synapse, at the T cell–antigen-presenting cell contact site. Surface receptors and signaling components are progressively recruited into this domain where they are organized in defined three-dimensional structures. To better understand how TCR are supplied to the signaling domain during the activation process, we measured (using confocal microscopy and photo-bleaching recovery techniques) lateral mobility of GFP-tagged TCR on living Jurkat cell surface. We show that: (i) surface-expressed TCR exhibit an intrinsic, actin cytoskeleton-independent, lateral mobility which allows them to passively diffuse over the entire T cell surface within ~60 min and (ii) non-stimulated TCR rapidly enter the signaling domain. Our results indicate that TCR lateral mobility per se is sufficient to ensure TCR supply to the immunological synapse in the course of sustained T cell activation.
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T cell-based immunotherapy has demonstrated great therapeutic potential in recent decades, on the one hand, by using tumor-infiltrating lymphocytes (TILs) and, on the other hand, by engineering T cells to obtain anti-tumor specificities through the introduction of either engineered T cell receptors (TCRs) or chimeric antigen receptors (CARs). Given the distinct design of both receptors and the type of antigen that is encountered, the requirements for proper antigen engagement and downstream signal transduction by TCRs and CARs differ. Synapse formation and signal transduction of CAR T cells, despite further refinement of CAR T cell designs, still do not fully recapitulate that of TCR T cells and might limit CAR T cell persistence and functionality. Thus, deep knowledge about the molecular differences in CAR and TCR T cell signaling would greatly advance the further optimization of CAR designs and elucidate under which circumstances a combination of both receptors would improve the functionality of T cells for cancer treatment. Herein, we provide a comprehensive review about similarities and differences by directly comparing the architecture, synapse formation and signaling of TCRs and CARs, highlighting the knowns and unknowns. In the second part of the review, we discuss the current status of combining CAR and TCR technologies, encouraging a change in perspective from “TCR versus CAR” to “TCR and CAR”.
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Cancer Immunotherapy
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