Effectors against infection 2

• Describe the activation of CD4+ and CD8+ T cells

  Both require recognition of an antigen to be activated:

  • CD4+ T cells: MHCII expressed by antigen presenting cells, commonly dendritic cells
  • CD8+ T cells: MHCI expressed by all nucleated cells, but still require initial priming by dendritic cells

  Both require co-stimulation to be activated:

  • CD4+ and CD8+ T cells: dendritic cell, e.g., CD28 with CD80/86

  CD4+ T cells can produce cytokines that activate CD8+ T cells and vice versa.
• Outline the action of CD4+ T cells

  CD4+ T cells do not generally kill pathogens or infected cells directly, instead they function by helping other parts of the immune system operate, hence their name.
• How do CD4+ T helper 1 cells regulate macrophage responses?

  CD4+ T helper cells are generally used in the killing of intracellular pathogens. In some infections, these intracellular pathogens can infect macrophages, rendering them inactive. Th cells secrete IFN-gamma, which enhances CD40 ligand and CD40 receptor interaction, leading to activation of macrophages and upregulation of MHCII, which consequently increases T cell activation. This occurs more slowly over a period of hours.

  
• Describe how CD4+ T helper 1 cells upregulate immune responses.

  CD4+ T helper 1 cells can produce cytokines to stimulate immune responses, for example:

  • IL-3 and GM-CSF: induce macrophage differentiation in the bone marrow
  • IL-2: induces T cell proliferation
  • Fas ligand: kills chronically infected cells, which leads to release of bacteria to be destroyed by macrophages
  • Stimulate antibody production in low levels
  • Opsonise pathogens in their extracellular phase
• Describe how CD4+ T helper 2 cells upregulate immune responses.

  CD4+ T helper 2 cells generally deal with extracellular pathogens by:

  1. Helping B cells produce antibody by secreting IL-4 and IL-5, which stimulate B cell proliferation and differentiation, leading to IgE production.
  2. Activates basophils, eosinophils and mast cells either directly through secretion of cytokines or indirectly via stimulation of IgE production by B cells.
• Describe how CD4+ T helper 17 cells regulate immune responses.

  CD4+ T helper 17 cells generally act against extracellular bacteria and fungi by producing:

  • IL-17: induces cytokine and chemokine production in several cells, which results in neutrophil recruitment and stimulation of macrophage and neutrophil production in bone marrow
  • IL-22: induces antimicrobial peptide production
• Describe how CD8+ cytotoxic T cells kill an infected cell

  Cytotoxic T cells induce apoptosis in specific cells, this process is very quick (within a range of minutes). Apoptosis produces less damage than necrosis, which minimises inflammation.

  1. Cytotoxic T cells bind loosely to a target cell
  2. CTL recognises antigen presented by MHCI
  3. Its cytoskeleton reorganises to place granules at the site of contact.
  4. CTL releases cytotoxic granules at the point of cell contact, facilitating specific killing.
• Describe how CD8+ cytotoxic T cells induce apoptosis in infected cells.

  CTL cells release granules into the infected cell containing:

  • Granzymes: serine proteases that induce apoptosis in target cell
  • Granulysin: antimicrobial and can induce apoptosis
  • Perforin: forms pores in order to help deliver granule contents to target cell
• Describe how CD8+ cytotoxic T cells can regulate other aspects of the immune response

  Cytotoxic T cells can produce cytokines that regulate immune response:

  • IFN-gamma: activates macrophages, increases MHCI expression in infected cells and directly inhibits viral replication
  • TNF-alpha: helps IFN-gamma activate and can help directly kill some infected cells

  CD8+ CTLs cooperate with CD4+ T helper cells to coordinate responses against intracellular pathogens.

  
• Describe how antibodies neutralise pathogens

  Antibodies can bind directly to pathogens or toxins to prevent attachment and entry into the cell.

  
• Describe how antibodies mediate agglutination of pathogens

  Antibodies bind to pathogens to form a lattice, causing clumping of the particles. This increases phagocytosis and forms immune complexes, which activates the complement pathway via binding of C1q.

  
• Describe how antibodies mediate opsonisation of pathogens

  Antibodies, specifically IgG, coat bacterium alongside complement. C3b coating the bacterium then binds to complement receptor 1 on macrophages and antibody binds to Fc receptor so that the bacterium is phagocytosed.

  
• Describe antibody dependent cell mediated cytotoxicity

  Antibodies can bind to infected cells or large extracellular pathogen and form bridges to immune cells, by binding to their Fc receptors, such as natural killer cells or macrophages. This increases cell mediated death of the infected cells or pathogen.
• Describe how IgE mediates immune responses

  IgE activates mast cells, which leads to the release of granules and cytokines. This initiates an inflammatory response. IgE can also activate basophils and eosinophils.