3,439 research outputs found
Cytotoxic T Lymphocyte Antigen-4 Accumulation in the Immunological Synapse Is Regulated by TCR Signal Strength
AbstractCD28 and CTLA-4 engagement with B7 expressed by APCs generates critical regulatory signals for T cell activation. CD28 is expressed on the T cell surface and enhances T cell expansion, while CTLA-4 localizes primarily to an intracellular compartment and inhibits T cell proliferation. We demonstrate that CTLA-4 has several unique trafficking properties that may regulate its ability to attenuate a T cell response. Importantly, accumulation of CTLA-4 at the immunological synapse is proportional to the strength of the TCR signal, suggesting that cells receiving stronger stimuli are more susceptible to CTLA-4-mediated inhibition. This may represent a novel feedback control mechanism in which a stimulatory signal regulates the recruitment of an inhibitory receptor to a functionally relevant site on the cell surface
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Toward an Objective Characterization of an Anhedonic Phenotype: A Signal-Detection Approach
Background: Difficulties in defining and characterizing phenotypes has hindered progress in psychiatric genetics and clinical neuroscience. Decreased approach-related behavior and anhedonia (lack of responsiveness to pleasure) are considered cardinal features of depression, but few studies have used laboratory-based measures to objectively characterize these constructs. Methods: To assess hedonic capacity in relation to depressive, particularly anhedonic, symptoms, 62 participants completed a signal-detection task based on a differential reinforcement schedule. Anhedonia was operationalized as decreased reward responsiveness. Results: Unequal frequency of reward between two correct responses produced a response bias (i.e., a systematic preference to identify the stimulus paired with the more frequent reward). Subjects with elevated depressive symptoms (Beck Depression Inventory scores ≥ 16) failed to show a response bias. Impaired reward responsiveness predicted higher anhedonic symptoms 1 month later, after controlling for general negative affectivity. Conclusions: Impaired tendency to modulate behavior as a function of prior reinforcement might underline diminished hedonic capacity in depression. When applied to a clinical population, objective assessments of participants’ propensity to modulate behavior as a function of reward might provide a powerful tool for improving the phenotypic definition of depression and thus offer a reliable behavioral screening approach for neuroscience studies of depression.Psycholog
Rapid prediction of lab-grown tissue properties using deep learning
The interactions between cells and the extracellular matrix are vital for the
self-organisation of tissues. In this paper we present proof-of-concept to use
machine learning tools to predict the role of this mechanobiology in the
self-organisation of cell-laden hydrogels grown in tethered moulds. We develop
a process for the automated generation of mould designs with and without key
symmetries. We create a large training set with cases by running
detailed biophysical simulations of cell-matrix interactions using the
contractile network dipole orientation (CONDOR) model for the self-organisation
of cellular hydrogels within these moulds. These are used to train an
implementation of the \texttt{pix2pix} deep learning model, reserving
cases that were unseen in the training of the neural network for training and
validation. Comparison between the predictions of the machine learning
technique and the reserved predictions from the biophysical algorithm show that
the machine learning algorithm makes excellent predictions. The machine
learning algorithm is significantly faster than the biophysical method, opening
the possibility of very high throughput rational design of moulds for
pharmaceutical testing, regenerative medicine and fundamental studies of
biology. Future extensions for scaffolds and 3D bioprinting will open
additional applications.Comment: 26 Pages, 11 Figure
High-throughput design of cultured tissue moulds using a biophysical model
The technique presented here identifies tethered mould designs, optimised for
growing cultured tissue with very highly-aligned cells. It is based on a
microscopic biophysical model for polarised cellular hydrogels. There is an
unmet need for tools to assist mould and scaffold designs for the growth of
cultured tissues with bespoke cell organisations, that can be used in
applications such as regenerative medicine, drug screening and cultured meat.
High-throughput biophysical calculations were made for a wide variety of
computer-generated moulds, with cell-matrix interactions and tissue-scale
forces simulated using a contractile-network dipole-orientation model.
Elongated moulds with central broadening and one of the following tethering
strategies are found to lead to highly-aligned cells: (1) tethers placed within
the bilateral protrusions resulting from an indentation on the short edge, to
guide alignment (2) tethers placed within a single vertex to shrink the
available space for misalignment. As such, proof-of-concept has been shown for
mould and tethered scaffold design based on a recently developed biophysical
model. The approach is applicable to a broad range of cell types that align in
tissues and is extensible for 3D scaffolds
Cytotoxic T Lymphocyte–associated Antigen 4 (CTLA-4) Regulates the Unfolding of Autoimmune Diabetes
Evidence has been accumulating that shows that insulin-dependent diabetes is subject to immunoregulation. To determine whether cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) is involved, we injected anti–CTLA-4 mAb into a TCR transgenic model of diabetes at different stages of disease. When injected into young mice, months before they would normally become diabetic, anti–CTLA-4 induced diabetes rapidly and essentially universally; this was not the result of a global activation of T lymphocytes, but did reflect a much more aggressive T cell infiltrate in the pancreatic islets. These effects were only observed if anti–CTLA-4 was injected during a narrow time window, before the initiation of insulitis. Thus, engagement of CTLA-4 at the time when potentially diabetogenic T cells are first activated is a pivotal event; if engagement is permitted, invasion of the islets occurs, but remains quite innocuous for months, if not, insulitis is much more aggressive, and diabetes quickly ensues
Cutting edge: CTLA-4 on effector T cells inhibits in trans,”
CTLA-4 is thought to inhibit effector T cells both intrinsically, by competing with CD28 for B7 ligands, and extrinsically, through the action of regulatory T cells (Tregs). We studied in vivo responses of normal and CTLA-4-deficient Ag-specific murine effector CD4 + T cells. We directly demonstrate that effector T cellrestricted CTLA-4 inhibits T cell responses in a cellextrinsic manner. Cotransfer experiments show that CTLA-4 on normal effector CD4 + T cells completely abrogates the dramatically increased expansion normally experienced by their CTLA-4-deficient counterparts. Neither the wild-type nor the CTLA-4-deficient T cells express the Treg transcription factor Foxp3 when transferred alone or together. Thus, cell-extrinsic inhibition of T cell responses by CTLA-4 is not limited to Tregs but is also a function of effector T cells
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