147,480 research outputs found

    New simplified molecular design for functional T cell receptor

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    We have produced a chimeric single-chain T cell receptor (TcR) that combines the specific antibody recognition function and TcR/CD3 signaling properties within the same polypeptide chain. This hybrid molecule consisted of a single-chain antibody combining site that was connected over a short spacer to the transmembrane and cytoplasmic region of CD3. When expressed on TcR- or TcR+ T cell hybridomas it could mediate recognition of relevent target cells and subsequent production of lymphokines; i.e. it could functionally replace the TcR/CD3 complex. Therefore, the single-chain TcR model presented here represents an interesting and useful means for the creation of T cells with new specificities

    Co-receptor CD8-mediated modulation of T-cell receptor functional sensitivity and epitope recognition degeneracy

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    The interaction between T-cell receptors (TCRs) and peptide epitopes is highly degenerate: a TCR is capable of interacting productively with a wide range of different peptide ligands, involving not only cross-reactivity proper (similar epitopes elicit strong responses), but also polyspecificity (ligands with distinct physicochemical properties are capable of interacting with the TCR). Degeneracy does not gainsay the fact that TCR recognition is fundamentally specific: for the vast majority of ligands, the functional sensitivity of a given TCR is virtually null whereas this TCR has an appreciable functional sensitivity only for a minute fraction of all possible ligands. Degeneracy can be described mathematically as the probability that the functional sensitivity, of a given TCR to a randomly selected ligand, exceeds a set value. Variation of this value generates a statistical distribution that characterizes TCR degeneracy. This distribution can be modeled on the basis of a Gaussian distribution for the TCR/ligand dissociation energy. The kinetics of the TCR and the MHCI molecule can be used to transform this underlying Gaussian distribution into the observed distribution of functional sensitivity values. In the present paper, the model is extended by accounting explicitly for the kinetics of the interaction between the co-receptor and the MHCI molecule. We show that T-cells can modulate the level of degeneracy by varying the density of co-receptors on the cell surface. This could allow for an analog of avidity maturation during incipient T-cell responses

    Mechanisms of pattern formation during T cell adhesion

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    T cells form intriguing patterns during adhesion to antigen-presenting cells. The patterns at the cell-cell contact zone are composed of two types of domains, which either contain short TCR/MHCp receptor-ligand complexes or the longer LFA-1/ICAM-1 complexes. The final pattern consists of a central TCR/MHCp domain surrounded by a ring-shaped LFA-1/ICAM-1 domain, while the characteristic pattern formed at intermediate times is inverted with TCR/MHCp complexes at the periphery of the contact zone and LFA-1/ICAM-1 complexes in the center. In this article, we present a statistical-mechanical model of cell adhesion and propose a novel mechanism for the T cell pattern formation. Our mechanism for the formation of the intermediate inverted pattern is based (i) on the initial nucleation of numerous TCR/MHCp microdomains, and (ii) on the diffusion of free receptors and ligands into the contact zone. Due to this inward diffusion, TCR/MHCp microdomains at the rim of the contact zone grow faster and form an intermediate peripheral ring for sufficiently large TCR/MHCp concentrations. In agreement with experiments, we find that the formation of the final pattern with a central TCR/MHCp domain requires active cytoskeletal transport processes. Without active transport, the intermediate inverted pattern seems to be metastable in our model, which might explain patterns observed during natural killer (NK) cell adhesion. At smaller TCR/MHCp complex concentrations, we observe a different regime of pattern formation with intermediate multifocal TCR/MHCp patterns which resemble experimental patterns found during thymozyte adhesion.Comment: 12 pages, 8 figure
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