The T cell receptor Vβ6 domain imparts reactivity to the Mls-1a antigen
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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.
Immunological synapse
Jurkat cells
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Summary T‐cell activation results from engagement of the T‐cell receptor (TCR) by cognate peptide–major histocompatibility complex (pMHC) complexes on the surface of antigen‐presenting cells (APC). Previous studies have provided evidence supporting the notion that the half‐life of the TCR/pMHC interaction and the density of pMHC on the APC are two parameters that can influence T‐cell activation. However, whether the half‐life of the TCR/pMHC interaction can modulate T‐cell activation in response to a pathogen challenge remains unknown. To approach this question, we generated strains of bacteria expressing variants of the ovalbumin (OVA) antigen, carrying point mutations in the SIINFEKL sequence. When bound to H‐2K b , this peptide is the cognate ligand for the OT‐I TCR. Variants of the H‐2K b /SIINFEKL bind to the OT‐I TCR with distinct half‐lives. Here we show that dendritic cells (DCs) infected with bacteria expressing OVA variants were incapable of activating OT‐I T cells when the half‐life of the TCR/H‐2K b /OVA interaction was excessively short. Consistent with these data, T‐cell activation was only observed in mice infected with bacteria expressing OVA variants that bound to OT‐I with a half‐life above a certain threshold. Considered together, our data suggest that the half‐life of TCR/pMHC interaction can significantly modulate T‐cell activation in vivo , as well as influence recognition of antigens expressed by bacteria. These observations underscore the importance of the TCR/pMHC half‐life on the clearance of pathogens.
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CTLA-4, a negative regulator of T cell function, was found to associate with the T cell receptor (TCR) complex ζ chain in primary T cells. The association of TCRζ with CTLA-4, reconstituted in 293 transfectants, was enhanced by p56 lck -induced tyrosine phosphorylation. Coexpression of the CTLA-4–associated tyrosine phosphatase, SHP-2, resulted in dephosphorylation of TCRζ bound to CTLA-4 and abolished the p56 lck -inducible TCRζ–CTLA-4 interaction. Thus, CTLA-4 inhibits TCR signal transduction by binding to TCRζ and inhibiting tyrosine phosphorylation after T cell activation. These findings have broad implications for the negative regulation of T cell function and T cell tolerance.
Dephosphorylation
Negative regulator
CTLA-4
Jurkat cells
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Abstract TCR interactions with cognate peptide-MHC (pepMHC) ligands are generally low affinity. This feature, together with the requirement for CD8/CD4 participation, has made it difficult to dissect relationships between TCR-binding parameters and T cell activation. Interpretations are further complicated when comparing different pepMHC, because these can vary greatly in stability. To examine the relationships between TCR-binding properties and T cell responses, in this study we characterized the interactions and activities mediated by a panel of TCRs that differed widely in their binding to the same pepMHC. Monovalent binding of soluble TCR was characterized by surface plasmon resonance, and T cell hybridomas that expressed these TCR, with or without CD8 coexpression, were tested for their binding of monomeric and oligomeric forms of the pepMHC and for subsequent responses (IL-2 release). The binding threshold for eliciting this response in the absence of CD8 (KD = 600 nM) exhibited a relatively sharp cutoff between full activity and no activity, consistent with a switchlike response to pepMHC on APCs. However, when the pepMHC was immobilized (plate bound), T cells with the lowest affinity TCRs (e.g., KD = 30 μM) responded, even in the absence of CD8, indicating that these TCR are signaling competent. Surprisingly, even cells that expressed high-affinity (KD = 16 nM) TCRs along with CD8 were unresponsive to oligomers in solution. The findings suggest that to drive downstream T cell responses, pepMHC must be presented in a form that supports formation of appropriate supramolecular clusters.
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