How T cells 'see' antigen

The Howard Hughes Medical Institute and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature Immunology (Impact Factor: 20). 04/2005; 6(3):239-45. DOI: 10.1038/ni1173
Source: PubMed

ABSTRACT T lymphocytes bearing alphabeta T cell receptors are pivotal in the immune response of most vertebrates. For example, helper T cells orchestrate antibody production by B cells as well as stimulating other cells, whereas cytotoxic T cells kill virally infected or abnormal cells. Regulatory T cells act to dampen responsiveness, and natural killer-like T cells monitor lipid metabolism. The specificity of these cells is governed by the alphabeta T cell receptors - antibody-like heterodimeric receptors that detect antigenic fragments (peptides) or lipids bound to histocompatibility molecules. Intriguing clues as to how these peculiar ligands are recognized have gradually emerged over the years and tell a remarkable story of biochemical and cellular novelty. Here we summarize some of the more recent work on alphabeta T cell receptor recognition and discuss the implications for activation.

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Available from: Michelle Krogsgaard, Sep 27, 2015
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    • "In our study, the panel of engineered specific TCRs demonstrated a correlation between T-cell activation and both functional avidity and half-life indicating that the TCRs displayed via this method fit the biophysical parameters of previously reported engineered TCRs (Stone et al., 2009; Corse et al., 2011). Discrepancies between previous studies have been reconciled by considering factors that also influence T cell sensitivity such as coreceptor expression (Holler and Kranz, 2003; Laugel et al., 2007; Jiang et al., 2011), TCR oligomerization (Boniface et al., 1998; Minguet et al., 2007), co-agonist peptides (Krogsgaard et al., 2005), conformational changes (Krogsgaard et al., 2003), and confinement time (Aleksic et al., 2010). Previous studies have compared different affinity complexes obtained by using the same TCR recognizing different pMHC complexes, restricted to different MHCs or by just comparing different TCRs altogether (Kersh et al., 1998; Tian et al., 2007; Chervin et al., 2009; Persaud et al., 2010). "
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    ABSTRACT: T cell receptors (TCRs) on T cells recognize peptide-major histocompatibility complex (pMHC) molecules on the surface of antigen presenting cells and this interaction determines the T cell immune response. Due to negative selection, naturally occurring TCRs bind self (tumor) peptides with low affinity and have a much higher affinity for foreign antigens. This complicates isolation of naturally occurring, high affinity TCRs that mediate more effective tumor rejection for therapeutic purposes. An attractive approach to resolve this issue is to engineer high affinity TCRs in vitro using phage, yeast or mammalian TCR display systems. A caveat of these systems is that they rely on a large library by random mutagenesis due to the lack of knowledge regarding the specific interactions between the TCR and pMHC. We have focused on the mammalian retroviral display system because it uniquely allows for direct comparison of TCR-pMHC-binding properties with T-cell activation outcomes. Through an alanine-scanning approach, we are able to quickly map the key amino acid residues directly involved in TCR-pMHC interactions thereby significantly reducing the library size. Using this method, we demonstrate that for a self-antigen-specific human TCR (R6C12) the key residues for pMHC binding are located in the CDR3β region. This information was used as a basis for designing an efficacious TCR CDR3α library that allowed for selection of TCRs with higher avidity than the wild-type as evaluated through binding and activation experiments. This is a direct approach to target specific TCR residues in TCR library design to efficiently engineer high avidity TCRs that may potentially be used to enhance adoptive immunotherapy treatments.
    Journal of immunological methods 03/2013; 392(1-2). DOI:10.1016/j.jim.2013.02.018 · 1.82 Impact Factor
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    • "Activation of T cell mediated immune responses plays an important role in a variety of processes, ranging from fighting bacterial and viral infections to the activation of autoimmune responses (Lanzavecchia and Sallusto, 2001; Smith-Garvin et al., 2009). For these activities to be initiated, T cells need to become activated via triggering of their T cell receptors by interaction with peptideloaded MHC molecules on professional antigen-presenting cells such as dendritic cells (Krogsgaard and Davis, 2005; Zehn et al., 2012). These peptides can either directly bind to cell surface exposed MHC molecules, or, alternatively, peptides can be generated intracellularly and be loaded onto MHC class I or class II molecules prior to transport to the cell surface (Pieters, 2000; Unanue, 2002). "
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    ABSTRACT: Coronin 1, which is a member of the evolutionary conserved coronin protein family that is highly expressed in all leukocytes is involved in the activation of the Ca(2+)/calcineurin signaling pathway following cell surface stimulation in T cells, B cells as well as macrophages. Mice deficient for coronin 1 have strongly reduced peripheral T cell numbers as a result of a lack of pro-survival signals for naïve T cells. Whether or not impaired antigen processing and presentation in the absence of coronin 1 expression contributes to this reduction of T cell numbers is unknown. We here show that coronin 1-deficient bone marrow-derived dendritic cells develop normally, and that wild type and coronin 1-deficient dendritic cells were equally able to induce antigen-specific proliferation of T cells. Furthermore, upon immunization, in vivo proliferation of adoptively transferred antigen-specific T cells was comparable in wild type and coronin 1-deficient mice. Finally, infection of wild type and coronin 1-deficient dendritic cells with an ovalbumin-expressing Listeria monocytogenes strain induced comparable levels of ovalbumin-specific T cells responses. Together these results suggest that coronin 1 is dispensable for antigen processing and presentation by dendritic cells.
    Molecular Immunology 10/2012; 53(4):379-386. DOI:10.1016/j.molimm.2012.09.002 · 2.97 Impact Factor
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    • "Clustering of the TCRs by antigen recognition aided by weak interactions with endogenous MHCp and the recruitment of co-receptor-bound Lck to the site of recognition would then start the signaling cascade (Krogsgaard and Davis, 2005; Gascoigne, 2008). Conformational changes have been proposed as a mechanism for signal transduction, but apart from movement in the CDRs during binding to MHCp, conformation change upon antigen binding has only been found as a movement of part of the Cα domain, in a region predicted to interact with CD3ε (Kjer-Nielsen et al., 2003; Beddoe et al., 2009). "
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    ABSTRACT: Recent data with CD8+ T cells show that the initial phase of T cell receptor (TCR) binding to MHC-peptide (MHCp) is quickly followed by a second, stronger, binding phase representing the binding of CD8 to the MHCp. This second phase requires signaling by a Src-family kinase such as Lck. These data point out two aspects of the initial stage of TCR signaling that have not yet been clearly resolved. Firstly, how and by which Src-family kinase, is the initial phosphorylation of CD3ζ accomplished, given that the Lck associated with the co-receptors (CD4 or CD8) is not yet available. Secondly, what is the mechanism by which the co-receptor is brought close to the bound TCR before the co-receptor binds to MHCp?
    Frontiers in Immunology 12/2011; 2:72. DOI:10.3389/fimmu.2011.00072
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