T cells selectively filter oscillatory signals on the minutes timescale.
Geoff P. O’Donoghue,Lukasz J. Bugaj,Warren Anderson,Kyle G. Daniels,David J. Rawlings,David J. Rawlings,Wendell A. Lim +6 more
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TLDR
The engineered T cells obtained from healthy human donors were engineered to respond to light as a stimulus by building an optogenetically controlled chimeric antigen receptor (optoCAR) and it was discovered that T cells respond to minute-scale oscillations of activation signal by stimulating optoCAR T cells with tunable pulse trains of light.Abstract:
T cells experience complex temporal patterns of stimulus via receptor-ligand-binding interactions with surrounding cells. From these temporal patterns, T cells are able to pick out antigenic signals while establishing self-tolerance. Although features such as duration of antigen binding have been examined, our understanding of how T cells interpret signals with different frequencies or temporal stimulation patterns is relatively unexplored. We engineered T cells to respond to light as a stimulus by building an optogenetically controlled chimeric antigen receptor (optoCAR). We discovered that T cells respond to minute-scale oscillations of activation signal by stimulating optoCAR T cells with tunable pulse trains of light. Systematically scanning signal oscillation period from 1 to 150 min revealed that expression of CD69, a T cell activation marker, reached a local minimum at a period of ∼25 min (corresponding to 5 to 15 min pulse widths). A combination of inhibitors and genetic knockouts suggest that this frequency filtering mechanism lies downstream of the Erk signaling branch of the T cell response network and may involve a negative feedback loop that diminishes Erk activity. The timescale of CD69 filtering corresponds with the duration of T cell encounters with self-peptide-presenting APCs observed via intravital imaging in mice, indicating a potential functional role for temporal filtering in vivo. This study illustrates that the T cell signaling machinery is tuned to temporally filter and interpret time-variant input signals in discriminatory ways.read more
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Optophysiology: Illuminating cell physiology with optogenetics
TL;DR: Optogenetics combines light and genetics to enable precise control of living cells, tissues, and organisms with tailored functions as mentioned in this paper , which has the advantages of noninvasiveness, rapid responsiveness, tunable reversibility, and superior spatiotemporal resolution.
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Modeling the Dynamics of T-Cell Development in the Thymus.
TL;DR: In this article, the authors review experimental strategies aimed at revealing quantitative and dynamic properties of T-cell development and how they have been implemented in mathematical modeling strategies that were reported to help understand the flexible dynamics of the highly dividing and dying thymic cell populations.
Journal ArticleDOI
Optogenetic Approaches for the Spatiotemporal Control of Signal Transduction Pathways.
TL;DR: Optogenetic tools are based on genetically encoded light-sensing proteins facilitating the precise spatiotemporal control of signal transduction pathways and cell fate decisions in the absence of natural ligands as discussed by the authors.
Journal ArticleDOI
Optogenetics for transcriptional programming and genetic engineering.
TL;DR: Optogenetics combines genetics and biophotonics to enable non-invasive control of biological processes with high spatio-temporal precision as discussed by the authors , where multiple genetically encoded non-opsin photosensory modules have been harnessed to modulate gene transcription, DNA or RNA modifications, DNA recombination, and genome engineering by utilizing photons emitting in the wide range of 200-1000 nm.
Journal ArticleDOI
Engineering CAR T cells for enhanced efficacy and safety
TL;DR: Recent improvements on the CAR and other non-CAR molecules aimed to enhance CAR T cell efficacy and safety are discussed and the development of different types of inducible CAR T cells that can be controlled by environmental cues and/or external stimuli are highlighted.
References
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Journal ArticleDOI
A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis.
Ann B. Begovich,Victoria E.H. Carlton,Lee Honigberg,Steven J. Schrodi,Anand P. Chokkalingam,Heather C. Alexander,Kristin G. Ardlie,Qiqing Huang,Ashley M. Smith,Jill M. Spoerke,Marion T. Conn,Monica Chang,Sheng Yung P Chang,Randall K. Saiki,Joseph J. Catanese,Diane U. Leong,Veronica Garcia,Linda B. McAllister,Douglas A. Jeffery,Annette Lee,Franak Batliwalla,Elaine F. Remmers,Lindsey A. Criswell,Michael F. Seldin,Daniel L. Kastner,Christopher I. Amos,John J. Sninsky,Peter K. Gregersen +27 more
TL;DR: It is shown that the risk allele of a missense SNP in PTPN22 disrupts the P1 proline-rich motif that is important for interaction with Csk, potentially altering these proteins' normal function as negative regulators of T-cell activation.
Journal ArticleDOI
A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes
Nunzio Bottini,Lucia Musumeci,Andres Alonso,Souad Rahmouni,Konstantina Nika,Masoud Rostamkhani,James P. MacMurray,Gian Franco Meloni,Paola Lucarelli,Maurizio Pellecchia,George S. Eisenbarth,David E. Comings,Tomas Mustelin +12 more
TL;DR: A single-nucleotide polymorphism in the gene (PTPN22) encoding the lymphoid protein tyrosine phosphatase (LYP), a suppressor of T-cell activation, is associated with type 1 diabetes mellitus (T1D).
Journal ArticleDOI
Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity
TL;DR: This chimeric receptor provides the T cell with an antibody-like specificity and is able to effectively transmit the signal for T-cell activation and execution of its effector function.
Journal ArticleDOI
Chimeric Receptors Containing CD137 Signal Transduction Domains Mediate Enhanced Survival of T Cells and Increased Antileukemic Efficacy In Vivo
Michael C. Milone,Jonathan D. Fish,Jonathan D. Fish,Carmine Carpenito,Richard G. Carroll,Gwendolyn K. Binder,David T. Teachey,David T. Teachey,Minu Samanta,Mehdi Lakhal,Brian S. Gloss,Gwenn Danet-Desnoyers,Dario Campana,James L. Riley,Stephan A. Grupp,Stephan A. Grupp,Carl H. June +16 more
TL;DR: It is suggested that incorporation of the CD137 signaling domain in CARs should improve the persistence of CARs in the hematologic malignancies and hence maximize their antitumor activity.
Journal ArticleDOI
CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs.
Lawrence R. Shiow,David B. Rosen,Naděžda Brdičková,Ying Xu,Jinping An,Lewis L. Lanier,Jason G. Cyster,Mehrdad Matloubian +7 more
TL;DR: Treatment with the IFN-α/β inducer polyinosine polycytidylic acid inhibited egress by a mechanism that was partly lymphocyte-intrinsic, and observations indicate that CD69 forms a complex with and negatively regulates S1P1 and that it functions downstream ofIFN- α/β, and possibly other activating stimuli, to promote lymphocyte retention in lymphoid organs.