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Cell-mediated immunity

Cell-mediated immunity. Live example: the viral infection. Intra- vs Extra-cellular . Immunity to microbes will be targeted towards the destruction of the free organism However, viruses are obligate intracellular organisms and therefore immunity to infection will aim to:

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Cell-mediated immunity

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  1. Cell-mediated immunity Live example: the viral infection

  2. Intra- vs Extra-cellular • Immunity to microbes will be targeted towards the destruction of the free organism • However, viruses are obligate intracellular organisms and therefore immunity to infection will aim to: 1) neutralise free virus and thus prevent further spread of the virus 2) kill infected cells or suppress viral replication in infected cells

  3. The first band of defence • The initial response to infection with a virus involves the innate immune system • Innate immune system is the aspects of the immune system that are not antigen-specific and do not require a period of education • Innate immunity involves the many physical barriers to infection such as skin, the secretions that cover mucosal surfaces and the harsh environment of the gut (low pH and proteolytic enzymes). [If breach to all this occurs….] • Many viruses trigger the complement cascade while a sub-population of lymphocytes, the natural killer or “NK” cells, lyse infected cells. The innate immune response restricts viral replication while the “adaptive” or “acquired” immune response develops

  4. Interferons • Virally infected cells release proteins known as interferons. • There are three families of interferons (IFNs), designated α, β and γ. • Virtually all nucleated cells are capable of producing IFN-α and IFN-β in response to infection while IFN-γ is produced predominately by NK cells and activated Th cells. • All types of interferon act directly on infected cells to suppress viral replication.

  5. Interferons

  6. Interferons • Interferons can suppress virus production during the first two days of infection while other components of the immune response develop • They will up-regulate expression of MHC I molecules • Thus, interferons increase the efficiency of presentation of viral antigens to cells of the immune system • IFN-α/β are potent stimulators of NK cell proliferation and cytotoxic activity • NK cells in turn will respond the IFN-α/β stimulation by producing IFN-γ and a number of other cytokines and chemokines

  7. Natural killer cells • Natural killer cells or “NK” cells are a sub-population of lymphocytes and are morphologically “large granular lymphocytes”. • They express neither the T-cell receptor nor surface immunoglobulin and are therefore not antigen-specific. • NK cells play an important role in the early immune response to viral infection and are capable of killing of both virus-infected cells and cells that have undergone malignant transformation. • NK cells are capable of killing infected cells via a non-antigen specific mechanism and thus are crucial in the early control of viral infection (and so is innate).

  8. Natural killer cells

  9. Natural killer cells • The cytotoxic activity of NK cells involves: i) The release of the pore-forming protein “perforin”. Perforin monomers assemble on the target cell membrane leading to the formation of a transmembrane pore. Degradative enzymes and other cytotoxic factors relased from the NK cell may then enter the target through the polyperforin channel. ii) The production of cytokines such as TNFα (tumour necrosis factor) and IFN-γ (interferon-γ). iii) Antibody-dependent cell-mediated cytotoxicity (ADCC). Once antibody production has been triggered, NK cells can kill target cells by ADCC .

  10. Adaptive immunity • An antigen-specific response involving cytotoxic T cells and B cells producing virus-specific immunoglobulin may take more than a week to develop. • This delay in the adaptive immune response arises as viral antigens must first be taken up by antigen presenting cells such as the Langerhans cells in the skin and the interdigitating dendritic cells in lymph nodes, processed and presented in conjunction with MHC class II molecules to helper (Th) T cells. • Th cells then produce cytokines necessary for the expansion of antigen-specific cytotoxic (Tc) T cells and B cells.

  11. Adaptive immunity

  12. Adaptive immunity • Antigen presenting cells such as follicular dendritic cells in the germinal centres of the lymph node follicles present surface bound antigen to primed B cells stimulating them to proliferate and differentiate into plasma cells. • Each of the T and B cell populations must expand to sufficient levels to generate an immune response to the virus. • The B cells must produce enough immunoglobulin to neutralise free virus while the cytotoxic T cells must migrate to the sites of infection and lyse the infected cells.

  13. Cytotoxic T response • Viral proteins synthesised within the infected cell (ie. endogenous proteins) are cleaved into short peptides (nine amino acids in length) by proteasomes. The peptides are then transported into the rough endoplasmic reticulum where they associate with MHC class I molecules. • The peptide-loaded MHC molecules are then transported to the cell surface. • Cytotoxic T cells (CD8+) recognise the MHC I / antigen complex via TcR and then lyse infected cells expressing viral peptides

  14. Cytotoxic T response

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