INTRODUCTION: T-cell receptor (TCR) recognition of foreign peptides presented by the major histocompatibility complex (MHC) initiates the adaptive immune response against pathogens. While a large number of TCR sequences specific to different antigenic peptides are known to date, the structural data describing the conformation and contacting residues for TCR-peptide-MHC complexes is relatively limited. In the present study we aim to extend and analyze the set of available structures by performing highly accurate template-based modeling of these complexes using TCR sequences with known specificity. METHODS: Identification of CDR3 sequences and their further clustering, based on available spatial structures, V- and J-genes of corresponding T-cell receptors, and epitopes, was performed using the VDJdb database. Modeling of the selected CDR3 loops was conducted using a stepwise introduction of single amino acid substitutions to the template PDB structures, followed by optimization of the TCR-peptide-MHC contacting interface using the Rosetta package applications. Statistical analysis and recursive feature elimination procedures were carried out on computed energy values and properties of contacting amino acid residues between CDR3 loops and peptides, using R. RESULTS: Using the set of 29 complex templates (including a template with SARS-CoV-2 antigen) and 732 specificity records, we built a database of 1585 model structures carrying substitutions in either TCRα or TCRβ chains with some models representing the result of different mutation pathways for the same final structure. This database allowed us to analyze features of amino acid contacts in TCR - peptide interfaces that govern antigen recognition preferences and interpret these interactions in terms of physicochemical properties of interacting residues. CONCLUSION: Our results provide a methodology for creating high-quality TCR-peptide-MHC models for antigens of interest that can be utilized to predict TCR specificity.
MHC-E regulates NK cells by displaying MHC class Ia signal peptides (VL9) to NKG2A:CD94 receptors. MHC-E can also present sequence-diverse, lower-affinity, pathogen-derived peptides to T cell receptors (TCRs) on CD8+ T cells. To understand these affinity differences, human MHC-E (HLA-E)-VL9 versus pathogen-derived peptide structures are compared. Small-angle X-ray scatter (SAXS) measures biophysical parameters in solution, allowing comparison with crystal structures. For HLA-E-VL9, there is concordance between SAXS and crystal parameters. In contrast, HLA-E-bound pathogen-derived peptides produce larger SAXS dimensions that reduce to their crystallographic dimensions only when excess peptide is supplied. Further crystallographic analysis demonstrates three amino acids, exclusive to MHC-E, that not only position VL9 close to the α2 helix, but also allow non-VL9 peptide binding with re-configuration of a key TCR-interacting α2 region. Thus, non-VL9-bound peptides introduce an alternative peptide-binding motif and surface recognition landscape, providing a likely basis for VL9- and non-VL9-HLA-E immune discrimination.
- MeSH
- CD8-Positive T-Lymphocytes MeSH
- X-Ray Diffraction MeSH
- Protein Conformation MeSH
- NK Cell Lectin-Like Receptor Subfamily C metabolism MeSH
- Humans MeSH
- Scattering, Small Angle MeSH
- Histocompatibility Antigens Class I * metabolism MeSH
- Peptides metabolism MeSH
- Protein Binding MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
The inevitability of evolution of the adaptive immune system with its mechanism of randomly rearranging segments of the T cell receptor (TCR) gene is the generation of self-reactive clones. For the sake of prevention of autoimmunity, these clones must be eliminated from the pool of circulating T cells. This process occurs largely in the thymic medulla where the strength of affinity between TCR and self-peptide MHC complexes is the factor determining thymocyte fate. Thus, the display of self-antigens in the thymus by thymic antigen presenting cells, which are comprised of medullary thymic epithelial (mTECs) and dendritic cells (DCs), is fundamental for the establishment of T cell central tolerance. Whereas mTECs produce and present antigens in a direct, self-autonomous manner, thymic DCs can acquire these mTEC-derived antigens by cooperative antigen transfer (CAT), and thus present them indirectly. While the basic characteristics for both direct and indirect presentation of self-antigens are currently known, recent reports that describe the heterogeneity of mTEC and DC subsets, their presentation capacity, and the potentially non-redundant roles in T cell selection processes represents another level of complexity which we are attempting to unravel. In this review, we underscore the seminal studies relevant to these topics with an emphasis on new observations pertinent to the mechanism of CAT and its cellular trajectories underpinning the preferential distribution of thymic epithelial cell-derived self-antigens to specific subsets of DC. Identification of molecular determinants which control CAT would significantly advance our understanding of how the cellularly targeted presentation of thymic self-antigens is functionally coupled to the T cell selection process.
The coreceptor CD8αβ can greatly promote activation of T cells by strengthening T-cell receptor (TCR) binding to cognate peptide-MHC complexes (pMHC) on antigen presenting cells and by bringing p56Lck to TCR/CD3. Here, we demonstrate that CD8 can also bind to pMHC on the T cell (in cis) and that this inhibits their activation. Using molecular modeling, fluorescence resonance energy transfer experiments on living cells, biochemical and mutational analysis, we show that CD8 binding to pMHC in cis involves a different docking mode and is regulated by posttranslational modifications including a membrane-distal interchain disulfide bond and negatively charged O-linked glycans near positively charged sequences on the CD8β stalk. These modifications distort the stalk, thus favoring CD8 binding to pMHC in cis. Differential binding of CD8 to pMHC in cis or trans is a means to regulate CD8+ T-cell responses and provides new translational opportunities.
- MeSH
- Lymphocyte Activation immunology MeSH
- CD8 Antigens chemistry genetics metabolism MeSH
- Models, Biological MeSH
- CD8-Positive T-Lymphocytes immunology metabolism MeSH
- Histocompatibility Antigens chemistry genetics immunology MeSH
- Protein Interaction Domains and Motifs MeSH
- Protein Conformation MeSH
- Models, Molecular MeSH
- Multiprotein Complexes chemistry immunology metabolism MeSH
- Mutation MeSH
- Mice, Knockout MeSH
- Mice MeSH
- Peptides chemistry immunology metabolism MeSH
- Amino Acid Sequence MeSH
- Protein Binding MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
... -- The Organization and Inheritance of MHC Genes • The MHC Locus Encodes the Three Major Classes of ... ... MHC Molecules -- 250 -- 250 -- The Role and Expression Pattern of MHC Molecules • MHC Molecules Present ... ... Are Generated by Protease Complexes Called Proteasomes • Peptides Are Transported from the Cytosol ... ... to the Rough Endoplasmic Reticulum • Chaperones Aid Peptide Assembly with MHC Class Molecules -- The ... ... Endocytic Vesicles • Peptides Assemble with MHC Class II Molecules by Displacing CLIP -- Unconventional ...
Eight edition různé stránkování : barevné ilustrace ; 28 cm
- MeSH
- Allergy and Immunology MeSH
- Immune System MeSH
- Publication type
- Textbook MeSH
- Conspectus
- Patologie. Klinická medicína
- Učební osnovy. Vyučovací předměty. Učebnice
- NML Fields
- alergologie a imunologie
The interaction of T-cell receptors (TCRs) with self- and non-self-peptides in the major histocompatibility complex (MHC) stimulates crucial signaling events, which in turn can activate T lymphocytes. A variety of accessory molecules further modulate T-cell signaling. Of these, the CD4 and CD8 coreceptors make the most critical contributions to T cell sensitivity in vivo. Whereas, CD4 function in T cell development is well-characterized, its role in peripheral T cells remains incompletely understood. It was originally suggested that CD4 stabilizes weak interactions between TCRs and peptides in the MHC and delivers Lck kinases to that complex. The results of numerous experiments support the latter role, indicating that the CD4-Lck complex accelerates TCR-triggered signaling and controls the availability of the kinase for TCR in the absence of the ligand. On the other hand, extremely low affinity of CD4 for MHC rules out its ability to stabilize the receptor-ligand complex. In this review, we summarize the current knowledge on CD4 in T cells, with a special emphasis on the spatio-temporal organization of early signaling events and the relevance for CD4 function. We further highlight the capacity of CD4 to interact with the MHC in the absence of TCR. It drives the adhesion of T cells to the cells that express the MHC. This process is facilitated by the CD4 accumulation in the tips of microvilli on the surface of unstimulated T cells. Based on these observations, we suggest an alternative model of CD4 role in T-cell activation.
- MeSH
- Lymphocyte Activation * MeSH
- CD4-Positive T-Lymphocytes cytology immunology MeSH
- CD8-Positive T-Lymphocytes cytology metabolism MeSH
- Histocompatibility Antigens immunology MeSH
- Humans MeSH
- Receptors, Antigen, T-Cell immunology MeSH
- Signal Transduction immunology MeSH
- Lymphocyte Specific Protein Tyrosine Kinase p56(lck) immunology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
... -cell surface receptor for antigen (BCR), 61 The T-cell surface receptor for antigen (TCR), 63 vi -- ... ... generation of diversity for antigen recognition, 67 NK receptors, 72 -- The major histocompatibility complex ... ... (MHC), 75 -- 5 The primary interaction with antigen, 86 -- What antibodies see, 86 Identifying ? ... ... for activation of naive CD8+ T-cells, 100 The nature of the \'groovy\' peptide, 101 -- The aß T-cell ... ... receptor forms a ternary complex with MHC and antigenic peptide, 103 T-cells with a different outlook ...
11th ed. xvi, 474 s. : il., tabs. ; 28 cm
... and Antigen Presentation to T Cells 15 2.1 Form of Antigen Recognized by T Cells 15 2.2 MHC Molecules ... ... 16 2.3 MHC Loci 16 2.4 Structure of MHC Molecules 18 2.5 Peptide Binding to MHC Molecules 19 2.5 a MHC ... ... 19 2.5 b MHC Class II 19 2.6 Antigen-Presenting Cells 20 2.7 Antigen Processing and MHC Association 20 ... ... Structure of T-Cell Receptors 25 3.3 Antigen Recognition by T-Cell Receptors 27 3.3 a Recognition of Peptide-MHC ... ... Complexes 27 3.3 b Recognition of Other Antigen Forms 27 3.4 Molecules that Enhance the TCR-Peptide-MHC ...
303 s. : il.
... 4.12 -- Structure of the «3 TCR Heterodimer 4.13 -- Structure of the TCR Complex 4.13 -- Structure of ... ... the yo TCR Heterodimer 4.14 -- Distribution of «3 and 78 forms of TCR 4.14 -- Major Histocompatibility ... ... 4.16 -- Genomic Organization of the MHC 4.17 -- MHC Polymorphism 4.19 -- 5. ... ... Processing and Presentation 6.9 -- Processing of Antigens 6.10 -- Structure of Class I Antigens 6.10 -- MHC-Peptide ... ... of Immune Complexes 21.11 -- 22. ...
3rd ed. přeruš. str. : barev. fot., obr., tab., grafy, přeruš. lit., rejstř. ; 28 cm
- MeSH
- Allergy and Immunology MeSH
- Immune System MeSH
- Communicable Diseases immunology MeSH
- Neoplasms immunology MeSH
- Conspectus
- Patologie. Klinická medicína
- NML Fields
- alergologie a imunologie
- infekční lékařství
- NML Publication type
- učebnice vysokých škol
