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ANTIGEN RECOGNITION BY T-LYMPHOCYTES

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

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ANTIGEN RECOGNITION BY T-LYMPHOCYTES

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  1. ANTIGEN RECOGNITION BY T-LYMPHOCYTES

  2. 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

  3. 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)

  4. 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)

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. STRUCTURE OF THE CD4 AND CD8 GLYCOPROTEINS • CD4 Structure • Four immunoglobulin-like domains (D1- D4) and a membrane-spanning region • CD8 Structure • Alpha, beta chain and extended membrane-spanning region

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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)

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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)

  27. 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

  28. 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)

  29. 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

  30. 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

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