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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

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antigen recognition by t lymphocytes2
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 lymphocytes3
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
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
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
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 genes9
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
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 complex12
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
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 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 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 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
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
major histocompatibility molecules mhc present antigens to cd4 and cd8 cells
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 cells25
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
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
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
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
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
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 pathogens37
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
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
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
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 pathogens44
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 pathogens45
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
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 cells49
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
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 mhc51
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
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 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 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
mhc polymorphism and rejection of transplanted tissues and organs
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
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