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THE MOST IMPORTANT FEATURES OF CYTOKINES The most important mediators of indirect cell communication in the immune system („hormones” of the immune system). Act in low concentrations. Cytokines can affect in an autocrine way, in a paracrine way, or in an endocrine way pleiotropic effect. Cytokines can act by synergistic or antagonistic ways to each other. A given cell may by affected by many cytokines resulting in the same effect redundant effect. - The responsiveness of the given cell is based on the expression of cytokine-specific receptors. ! Innate immunity as a first line of defence Innate immune cells recognize frequently found structures of pathogens, these are not found in human cells! Examples: duple strain RNA bacterial cell wall components bacterial flagellin…. Recognition is inevitable !! Danger signal! !! The innate immune system also recognizes molecules that are released from damaged or necrotic cells. Such molecules are called damage-associated molecular patterns (DAMPs). Specificity of innate immunity ( ) ! direct connetion between innate cells and pathogen Few receptors (20-30) are responsible for the recognition of all the pathogens INNATE IMMUNITY II Effector functions, elimination of pathogens 1. Phagocytosis 2. Killing with soluble mediators 3. Complement system 4. NK cell activation !! Monocite / macrofage PRR DC PRR Mast cell PRR Granulocites NK cell PRR Absence of MHCI Phagocy tosis Pathogen and cell killing Recogni -tion B cell T cell Complement Cell-cel (APC) Communi cation Soluble Phagocyto sis effector function Killing with solubl e mediat ors Killing with solu ble medi ators Pathogen Killing Monocita/ makrofág DC APC APC Hízó Sejt Granu locita NK sejt B-sejt Felis merés kommu nikáció Effektor funkció APC T-sejt Komp lement ! ! T helper cells (TH cells) assist other white blood cells in immunologic processes Cytotoxic T cells (TC cells, or CTLs) destroy virally infected cells and tumor cells Proteins are composed primarily of polypeptides (and often non-polypeptide cofactors. ) Peptides are short chains of amino acid monomers linked by peptide (amide) bonds. ANTIGEN RECOGNITION BY T-CELLS REQUIRES PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS THAT EXPRESS MHC MOLECULES !! T II soluble Ag Native membrane Ag Cell surface MHCpeptide complex Peptide antigen Cell surface peptides APC APC APC No T-cell response T-cell response Dendritic cells take up antigen in the tissues, migrate to peripheral lymphoid organs, and present foreign antigens to naive T cells. How can detect the immune system the intracellular pathogens? PRR Antigen presentation Display intracellular peptides on the surface of cells MHC Major histocompatibility comlex cell surface molecules mediate interactions of T cells with antigen presenting cells MHCI Expressed by all nucleated cells STRUCTURE OF CLASS I MHC MOLECULES PEPTIDE 2 3 1 2m ! ! MHCII ! ! Expressed by professional antigen presenting cells Macrophage, dendritic cell, B cell STRUCTURE OF CLASS II MHC MOLECULES PEPTIDE 1 1 2 2 MEMBRANE RECEPTORS Intracellular peptide binding capacity One binding site can accomodate multiple peptides Cleft geometry -chain -chain Peptide 2-M MHC class I accommodate peptides of 8-10 amino acids Peptide -chain MHC class II accommodate peptides of >13 amino acids CYTOSOL-DERIVED PEPTIDES ARE PRESENTED BY MHC-I FOR T-CELLS RECOGNITION OF EXOGENOUS AND ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES ! ! Tc Th TCR TCR Peptide Peptide MHCI MHCII Exogenous Ag Endogenous Ag APC Peptides of endogenous proteins (virus, tumor) bind to class I MHC molecules presented to cytotoxic T cells Peptides of exogenous proteins (toxin, bacteria, allergen) bind to class II MHC molecules presented to helper T cells MHC RESTRICTION T-sejt T-sejt TCR TCR M HC MHC MHC APC APC APC ! T-sejt TCR One single T-cell receptor can recognize a given MHC – peptid complex The TCR-specific peptide is recognized only when its presented with an MHC on which the TCR had been selected during its development in the thymus If the peptide binds to another MHC molecule no T-cell recognition occurs (by this T cell) If the same MHC molecule binds another peptide, no T-cell recognition occurs !! T cell receptor (TCR) recognizes peptide antigen and simultaneously also recognizes the MHC molecule that is displaying that peptide Specificity of innate immunity Specificity of T cells Tc Distinct T cell receptors Peptides derived from different microbes peptid Tc MHC APC APC ! Specificity of innate immunity ( ! direct connetion between innate cells and pathogen ) Specificity of T cells T Distinct T cell receptors peptid Peptides derived from different microbes APC T MHC APC No direct connetion between T cell and pathogen APC-T cell connection A given type of MHC is able to bind different peptides Does not distinguish self and nonself peptides ! B cell epitop T cell epitop B cells recognize: T cells recognize: proteins polysaccharides lipids DNS steroids drugs, etc peptides (8-23 amino acid) Tissue or soluble antigens ! ! only when these peptides are presented by MHC molecules on APC cells !! MHCI Displays intracellular antigens to cytotoxic T cells ER is the site of protein synthesis MHC molecules are also synthetised in ER Degradation of endogenous proteins takes place in the proteasomes, they are presented on MHC I Transporters associated with antigen processing (TAP1 & 2) Hydrophobic transmembrane domain Lumen of ER Peptide ER membrane Cytosol Peptide Peptide Peptide antigens from proteasome ATP-binding cassette (ABC) domain Transporter has preference for longer than 8 amino acid peptides with hydrophobic C termini. Degradation of endogenous proteins in (immune) proteasomes TAP: Transporter associated with antigen processing !! MHCII Displays extracellular antigens to helper T cells Professional phagocytic cells macrophages neutrophyl granulocytes dendrtitic cells !! the phagocytosed cells or molecules may modify the functions of the cell phagocytosis followed by enzymatic degradation Professional antigen presenting cells macrophages B lymphocytes dendrtitic cells they express MHCII molecules the protein degradation products (peptides) can be presented to T lymphocytes by MHC molecules !! 1 Recognition 2. Uptake 3. Peptide production 4. MHCII-peptide complex 5. Presentation Pathogen recognition by innate immune system 1. Directly via PRR 2. Indirectly via opsonization 1 Recognition 2. Uptake Phagocytosis 3. Peptide production ! Invariant chain (Ii) function: 1. Chaperon – Conformation 2. Blocking of the peptide binding 3. Transport of MHC complex Comparision of intracellular events of MHCI and MHCII pathways T cell recognition Peptide fragments Peptides associate to MHC Antigen prezenting cell Expression of peptide/MHC complex on the cell surface Recognition of peptide/MHC complex by TCR T cell RECOGNITION OF EXOGENOUS AND ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES ! ! Tc Th TCR TCR Peptide Peptide MHCI MHCII Exogenous Ag Endogenous Ag APC Peptides of endogenous proteins (virus, tumor) bind to class I MHC molecules presented to cytotoxic T cells Peptides of exogenous proteins (toxin, bacteria, allergen) bind to class II MHC molecules presented to helper T cells