Major Histocompatibility Complex and T Cell Receptor

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Major Histocompatibility Complex and T Cell Receptor. Major Histocompatibility Complex: History. Transplantation: graft rejection Immune responses: antibody formation Highly polymorphic Bind peptide: recognized by T cells Three-dimensional structure determined by X-ray crystallography. α1. - PowerPoint PPT Presentation

Transcript of Major Histocompatibility Complex and T Cell Receptor

  • Major Histocompatibility Complex and T Cell Receptor

  • Major Histocompatibility Complex: HistoryTransplantation: graft rejectionImmune responses: antibody formationHighly polymorphicBind peptide: recognized by T cellsThree-dimensional structure determined by X-ray crystallography

  • Structure of Class I MHC

  • Structure of Class I MHCTwo polypeptide chains, a long chain and a short chain, called 2 microglobulin Four regions:Peptide-binding region - a groove formed from 1 and 2 domains of the chain 2. Immunoglobulin-like region highly conserved 3 domain - site to which CD8 on T cell binds

  • Structure of Class I MHC(continued)Transmembrane region stretch of hydrophobic amino acids spanning membraneCytoplasmic region contains sites for phosphorylation and binding to cytoskeletal elements

  • Structure of Class I MHC

  • Structure of Class I MHC Peptide-binding Regiona groove composed of an -helix on two opposite walls and eight -pleated sheets forming the floorresidues lining groove most polymorphicpeptide in groove 8-10 amino acids longspecific amino acid on peptide required for anchor site in groove

  • Variability For Polymorphism

  • Structure of Class II MHC

  • Structure of Class II MHCTwo polypeptide chains, and , of roughly equal length. Four regions:Peptide-binding region a groove formed from the 1 and 1 domains of the and chains site of polymorphismImmunoglobulin-like region conserved 2 and 2 domains 2 is site to which CD4 on T cell binds

  • Structure of Class II MHC(continued)Transmembrane region stretch of hydrophobic amino acids spanning membraneCytoplasmic region contains sites for phosphorylation and binding to cytoskeletal elements

  • Structure of Class II MHC

  • Variability For Polymorphism

  • Peptide-binding grooves for class I and class II MHC are structurally similarBoth have a peptide-binding groove with a wall of two helices and a floor of eight -pleated sheetsClose-ended groove for class I MHC requires an 8-10 amino acid-length peptide to bind; open-ended groove for Class II MHC lets it bind a peptide 13-25 amino acids long, not all of which lie in the grooveAnchor site rules apply to both classes

  • Aspects of MHCMHC molecules are membrane-bound. Recognition by T cells requires cell-cell contact.Peptide from cytosol associates with class I MHC and is recognized by Tc cells. Peptide from vesicles associates with class II MHC and is recognized by Th cells.

  • Aspects of MHC (continued)Although there is a high degree of polymorphism for a species, an individual has maximum of six different class I MHC products and only slightly more class II MHC products. A peptide must associate with a given MHC of that individual, otherwise no immune response can occur. That is one level of control.

  • Aspects of MHC (continued)Mature T cells must have a T cell receptor that recognizes the peptide associated with MHC. This is the second level of control.Each MHC molecule has only one binding site. The different peptides a given MHC molecule can bind all bind to the same site, but only one at a time.

  • Aspects of MHC (continued)MHC polymorphism is determined only in the germline. There are no recombinational mechanisms for generating diversity.Because each MHC molecule can bind many different peptides, binding is termed degenerate. Cytokines (especially interferon-) increase level of expression of MHC.

  • Aspects of MHC (continued)Alleles for MHC genes are co-dominant. Each MHC gene product is expressed on the cell surface of an individual nucleated cell.Why the high degree of polymorphism?Survival of species!

  • Structure of T Cell Receptor

  • Structure of T Cell Receptor (TCR)Two polypeptide chains, and , of roughly equal lengthBoth chains consist of a variable (V) and a constant (C) region chain V region has a joining (J) segment chain V region has both a J and diversity (D) segment

  • Structure of T Cell Receptor(continued)Hypervariable regions in V contribute to diversity of TCRTCR recognizes portions of MHC molecule and peptide bound in the grooveSmall population of T cells has a TCR comprised of and chains TCR specificity differs from TCR

  • Structure of T Cell Receptor

  • Properties of Ig and TCR Genes Ig TCRMany VDJs, few Cs yes yesVDJ rearrangement yes yesV-pairs form antigen yes yes recognition siteSomatic hypermutation yes no

  • Properties of Ig and TCR Proteins Ig TCR Transmembrane forms yes yesSecreted forms yes noIsotypes with different yes no functionsValency 2 1

  • CD3 ComplexGroup of four proteins associated with TCRConsists of a , a , two , and two chainsAll four proteins are invariantFunctions: 1) synthesized co-ordinately with TCR, required to bring TCR to surface 2) transduces activating signals to T cell when TCR recognizes MHC-peptide

  • CD3 Complex With TCR

  • Accessory Molecules Involved in Cell-Cell Interactions T cell surface molecules that engage with ligand on 2nd cell when TCR recognizes MHC-peptide T Cell Ligand on 2nd Cell CD4 class II MHC (2 domain) CD8 class I MHC (3 domain) LFA-2 LFA-3 LFA-1 ICAM-1, ICA-2 LFA = Leukocyte Function-associated AntigenICAM = InterCellular Adhesion Molecule

  • Accessory MoleculesAll are invariantIncrease adhesion between two engaged cells Some show increased expression in response to cytokines

  • Costimulatory MoleculesMolecules on T cell and 2nd cell that engage to deliver 2nd signal required for activation of T cellMost important costimulatory molecules: T cell Ligand on 2nd cell CD28 B7-1 (CD80), B7-2 (CD86)

  • Interactions of Th Cell and APCLFA-3LFA-2LFA-1TCRCD4ICAM-1Class IIMHCB7-1/B7-2(CD80/CD86CD28IL-1IL-6TNF-alphaIL-12IL-15TNF-betaIFN-gammaGM-CSFIL-4T helperlymphocyteAntigen-presentingcell

  • Interactions of Tc Cell and Target CellLFA-1TCRCD8ICAM-1Class IMHCLFA-3LFA-2T cytotoxiclymphocyteTargetcell