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ANTIGEN RECOGNITION BY T-LYMPHOCYTES ANTIGEN RECOGNITION BY T-LYMPHOCYTES * Antigens are recognized by cell surface receptors * Antigen receptor referred to as * T-cell receptor * T-cell and B-cell receptors are similar * Structure * Immunoglobulin superfamily * Organization of genes * Non-functional segments * Mechanism which generates diversity and specificity * Somatic recombination ANTIGEN RECOGNITION BY T-LYMPHOCYTES * T-cell and B-cell receptors recognize different antigens * B-cells recognize * Intact protein, carbohydrate and lipid molecules on bugs and soluble toxins * T-cells recognize * Peptide antigens bound to special antigen-presenting glycoproteins * Antigen-presenting glycoproteins * Major histocompatibility complex (MHC) molecules * Expressed on antigen-presenting cells (APC’s) T-LYMPHOCYTE (CELL) RECEPTOR * Membrane bound glycoprotein * Composed to 2 polypeptide chains (1 antigen binding site) * Alpha * Beta * Each chain has variable domain, constant domain and transmembrane region * Variable (V) domains of alpha and beta chains each have 3 hypervariable regions (loops) * Complementarity-determining regions (CDR) * Structure resembles single antigen-binding arm of B cell receptor (immunoglobulin) * Fab fragment (membrane-bound) GENERATION OF DIVERSITY IN T-CELL AND B-CELL RECEPTORS * Mechanisms which generate B-cell receptor diversity * Before antigen stimulation * Somatic recombination * After antigen stimulation * Somatic hypermutation * Mechanisms which generate T-cell receptor diversity * Before antigen stimulation * Somatic recombination * After antigen stimulation * None ORGANIZATION AND REARRANGEMENT OF T-CELL RECEPTOR GENES * Alpha chain locus * Located on chromosome 14 * Variable domain similar to IG light chain locus * V and J segments * Beta chain locus * Located on chromosome 7 * Variable domain similar to IG heavy chain locus * V, J and D segments * Receptor gene rearrangement takes place during T-cell development in thymus ORGANIZATION AND REARRANGEMENT OF T-CELL RECEPTOR GENES * Recombination directed by * Recombination signal sequences (RSS) * Alpha chain gene * V segment joined to J segment by somatic recombination * P and N nucleotides inserted at VJ junction * Beta chain gene * D segment joined to J segment * DJ segment joined to V segment * P and N nucleotides inserted at D, J and V junctions COMPOSITION OF THE T-CELL RECEPTOR COMPLEX * Newly synthesized alpha and beta chains enter endoplasmic reticulum * In ER, chains associate with 4 invariant membrane proteins * Chromosome 11 * Delta, epsilon, gamma * Chromosome 1 * Zeta * Invariant membrane proteins * Transport to cell surface * Signal transduction COMPOSITION OF THE T-CELL RECEPTOR COMPLEX * Delta, epsilon and gamma proteins collectively termed * CD3 complex * T-cell receptor complex * T-cell receptor, CD3 proteins and Zeta protein * Persons may lack CD3 delta or CD3 epsilon chains * Inefficient transport of receptors to cell surface * Low number of receptors * Impaired signal transduction ALTERNATIVE FORM OF T-CELL RECEPTOR * Second type of receptor consists of * Gamma and Delta chains * T-cells referred to as * Gamma:Delta T-cells * Gamma:Delta T-cells * Comprise approximately 1 to 5% of circulating T-cells * Function is unknown * Not restricted to MHC presentation of peptide antigens * Alpha:Beta and Gamma:Delta receptors never expressed together T CELL RECOGNITION OF ANTIGENS – PROCESSING AND PRESENTATION * T-cells cannot recognize antigens in native form * T-cell recognition of antigens * Processing * Presentation * Antigen Processing * Pathogen derived proteins broken down into peptides * Antigen Presentation * Peptide combined with MHC molecule and displayed on surface of antigen presenting cells T-CELLS RESPOND TO INTRACELLULAR AND EXTRACELLULAR PATHOGENS * T-cells classified on basis of cell surface glycoproteins * CD4 * CD8 * Classes have different functions * CD8 * Primary function to kill cells (cytotoxic) infected with virus or other intracellular pathogen * CD4 * Primary function to help other cells of immune system respond to extracellular pathogens CD4 T-CELLS RESPOND TO EXTRACELLULAR PATHOGENS * CD4 cells also known as T-helper cells * Subclasses of CD4 cells * T-helper 1 cells (TH1) * Activate tissue macrophages * T-helper 2 cells (TH2) * Stimulate B-cell proliferation and differentiation * Activation and stimulation mediated by cytokines STRUCTURE OF THE CD4 AND CD8 GLYCOPROTEINS * CD4 Structure * Four immunoglobulin-like domains (D1- D4) and a membranespanning region * CD8 Structure * Alpha, beta chain and extended membrane-spanning region MAJOR HISTOCOMPATIBILITY MOLECULES (MHC) PRESENT ANTIGENS TO CD4 AND CD8 CELLS * Classes of MHC molecules * MHC class I * MHC class II * Functions of MHC molecules * MHC class I * Present intracellular antigens to CD8 cells * MHC class II * Present extracellular antigens to CD4 cells MAJOR HISTOCOMPATIBILITY MOLECULES (MHC) PRESENT ANTIGENS TO CD4 AND CD8 CELLS * Mechanisms for recognition between T cells and MHC molecules * T-cell receptor recognition of peptide presented by MHC molecule * Specific interactions between * CD8 and MHC class I molecules * CD4 and MHC class II molecules * CD8 and CD4 molecules * Considered T-cell co-receptors STRUCTURES OF MHC MOLECULES * MHC molecules are glycoproteins * MHC class I molecule * A single membrane bound alpha chain non-covalently bonded to beta2-microglobulin * Alpha chain has three domains * MHC class II molecule * Two membrane bound chains (alpha and beta) * Each chain has two domains PEPTIDE BINDING SITES OF MHC MOLECULES * MHC molecule binding sites * Can bind many different amino acid sequences * Length of peptides bound * MHC class I * 8 – 10 amino acids * MHC class II * 13 – 25 amino acids PROCESSING OF ANTIGENS FROM INTRACELLULAR AND EXTRACELLULAR PATHOGENS * Intracellular pathogens * Degradation of proteins in cytosol of infected cells * Peptides enter endoplasmic reticulum and bound to MHC class I molecules * Extracellular pathogens * Microorganisms and toxins taken into cells by * Phagocytosis and endocytosis * Degradation of proteins and binding to MHC class II molecules in phagolysosomes and endocytotic vesicles MECHANISM FOR PROCESSING OF ANTIGENS FROM INTRACELLULAR PATHOGENS * Proteins degraded in cytosol of infected cells by * Proteasome * Proteasome * Barrel shaped protein complex with several proteolytic activities * Peptides transported across ER membrane by protein * Transporter associated with antigen processing (TAP) MECHANISM FOR PROCESSING OF ANTIGENS FROM INRACELLULAR PATHOGENS * MHC class I heavy chain enters ER and binds to membrane protein * Calnexin * Calnexin released when beta-2-microglobulin binds * MHC class I molecule binds complex of proteins * Peptide-loading complex * Calreticulin, Tapasin, TAP, ERp57 and PDI MECHANISM FOR PROCESSING OF ANTIGENS FROM INTRACELLULAR PATHOGENS * MHC class I molecule retained in ER until it binds a peptide * Following binding, MHC class I molecule * Released from protein complex * Leaves ER in membrane-bound vesicle * Transported by Golgi complex to cell surface * Process is continuous, not only during infection FAILURE OF THE INTRACELLULAR PATHOGEN PROCESSING MECHANISM * Bare Lymphocyte Syndrome (MHC class I) * Immunodeficiency disease * Clinical Manifestations * Chronic bacterial respiratory infections * Cutaneous ulceration with vasculitis * Mechanism * Mutations in TAP1 or TAP2 genes * Decreased levels of cell surface MHC class I molecules * Reduce levels of alpha:beta CD8 T cells MECHANISMS PREVENTING THE PROCESSING OF ANTIGENS FROM INTRACELLULAR PATHOGENS * Herpes Simplex Virus (HSV) * Produce protein which binds to and inhibits TAP * Prevents viral peptide transfer to ER * Adenovirus * Produce protein which binds MHC class I molecule * Prevents MHC class I molecule from leaving ER MECHANISM FOR PROCESSING ANTIGENS FROM EXTRACELLULAR PATHOGENS * Extracellular microorganisms and toxins engulfed by phagocytosis / endocytosis in * Phagosomes / endosomes * Phagosomes fuse with lysosomes (proteases/hydrolases) forming phagolysosome * Peptides produced bind with MHC class II molecules within vesicular system * Peptide:MHC class II complexes transported to cell surface MECHANISM FOR PROCESSING ANTIGENS FROM EXTRACELLULAR PATHOGENS * MHC class II alpha and beta chains transported into ER * In ER, associated with “invariant chain” which functions * Prevent peptide binding * Chaperones MHC II molecules to endosomes * In endosomes, invariant chain degraded by * Cathepsin L * Degradation results in small fragment which covers MHC II peptide binding site * Class II associated invariant chain peptide (CLIP) MECHANISM FOR PROCESSING ANTIGENS FROM EXTRACELLULAR PATHOGENS * CLIP removal associated with * Interaction of MHC II and endosome membrane glycoprotein * HLA-DM * HLA-DM * Similar structure to MHC II * Does not bind peptides or appear on cell surface * MHC II quickly binds peptide or is degraded * Peptide:MHC II transported to cell surface for recognition by specific T-cell receptor EXPRESSION OF MHC I AND MHC II ON HUMAN CELLS * MHC class I * Guard the intracellular territory * Constitutive expression on virtually all cells * Comprehensive surveillance by CD8 T-cells * MHC class II * Guard the extracellular territory * Constitutive expression only on APC’s * Macrophages * B lymphocytes * Dendritic cells (immature) EXPRESSION OF MHC I AND MHC II ON HUMAN CELLS * Antigen uptake by APC’s * Macrophages * Phagocytosis and pinocytosis in all tissues * B lymphocytes * Internalize antigens bound to surface IG * Receptor-mediated endocytosis * Dendritic cells (immature) * Phagocytosis and macropinocytosis in all tissues * Cytokine upregulation of MHC I and II in immune response * Interferons MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) * Named MHC following identification of region responsible for rejection of tissue or organ transplant * MHC molecules encoded by a number of closely linked genes on chromosome 6 * Conventional gene configuration * Large number of variants in human population * Variants responsible for * Host versus graft * Graft versus host MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) * Complex also called * Human leukocyte antigen (HLA) complex * Antibodies originally used to identify MHC molecules react with leukocytes * HLA I genes and HLA II genes * Located on short arm of chromosome 6 * Beta-2-microglobulin (C-15) and invariant chain (C-5) not located in HLA region MECHANISMS OF DIVERSITY IN MHC MOLECULES * Polygeny (polygenic) * Multiple genes encode alpha chain of MHC I molecules * Multiple genes encode alpha and beta chains of MHC II molecules * Polymorphism (polymorphic) * Multiple alternative forms of MHC I and MHC II genes in human population * Alternative gene forms called “alleles” POLYGENY AND POLYMORPHISM IN HUMAN MHC CLASS I MOLECULES * Polygeny (multiple genes) * 3 genes for alpha chain * HLA-A, HLA-B and HLA-C * Polymorphism (multiple alleles) * Alleles * HLA-A (506) * HLA-B (872) * HLA-C (274) POLYGENY AND POLYMORPHISM IN HUMAN MHC CLASS II MOLECULES * Polygeny (multiple genes) * HLA-DP * 1 gene for each alpha and beta chian * HLA-DQ * 1 gene for each alpha and beta chain * HLA-DR * 1 gene for alpha chain * DRA * 4 genes for beta chain * DRB1, DRB3, DRB4, DRB5 * Polymorphism (alleles) * Multiple alleles for all genes except DRA Figure 3-23 MHC POLYMORPHISM AND REJECTION OF TRANSPLANTED TISSUES AND ORGANS * MHC molecules primary reason for transplant rejection * Allogeneic * Genetic differences between two members of same species * Alloantigens * Antigens which differ between members of same species * Alloreaction * Immune response to alloantigens * MHC allotype variation is clustered in peptide binding site HUMAN LEUKOCYTE ANTIGEN (HLA) COMPLEX * HLA type * Combination of HLA class I and HLA class II allotypes * HLA typing in medicine * Selection of donors and recipients for transplantation * Transplantation of organs * Problem of graft rejection by recipient * HLA mismatches overcome using immunosuppressive agents * Transplantation of bone marrow * Problem of alloreaction of graft against recipients tissues