Lecture 13 - Cytotoxic Killer T cells

• Three-cell signal for CD8 T cell activation and differentiation to CTL


  • Signal 1: TcR-MHC/p interaction
  • Signal 2: Co-stimulatory molecules
  • Signal 3: CD40-CD40L interaction
  • Signal 4: CD137-CD137L interaction
• Naïve CD8 T cell activation

  1. Recognition of peptide-MHC complexes by the T cell receptor (TcR)

  2. Interaction with co-stimulatory molecules (CD28 on CD8 T cell, CD80/86 on APC)

  3. Interaction between CD40 on APC and CD40L on CD8 T cell

  4. Interaction between CD137 on CD8 T cell and CD137L on APC
• Cytotoxic T cell killers (CTLs)

  • Rapid and highly specific killing of target cells
  • Ability to serially kill many target cells
  • Release of weaponry at the site of infection
  • Importance of specificity for non-renewing cells, such as neurons
• Perforin


  Delivers contents of granules to target cell cytosol
• Granzymes


  Serine proteases that activate apoptosis once in the cytoplasm
• Granulysins


  Exhibit anti-microbial activity (in humans only)
• Intrinsic Pathway of Caspases

  1. Release of cytochrome c from the mitochondria

  2. Bcl-2 (anti-apoptotic) prevents Bax (pro-apoptotic) from binding to mitochondria

  3. Granzyme B binds and activates Bid (pro-apoptotic), leading to the release of Bax

  4. Bax self-polymerises and produces pores in the mitochondria membrane, resulting in the release of cytochrome c

  5. Caspases, including initiator caspase 9 and effector caspases (e.g., caspase 3), are activated

  6. Caspase 9 activates a chain reaction of caspase activation
• Extrinsic Pathway of Caspases


  1. Fas triggers apoptosis via a death domain

  2. Fas-Associated protein with Death Domain (FADD) acts as an adaptor protein with procaspase 8 to form the Death Inducing Signal Complex (DISC)

  3. This leads to the activation of initiator and executioner caspases
• Caspases


  Cysteine proteases that cleave their substrates and can be classified as initiators and effectors
• Phagocytic Removal


  Apoptotic bodies formed during apoptosis are quickly removed by phagocytes of the immune system to prevent tissue autoimmunity
• Contraction of CTL


  1. Decrease in the number of CTL in the body as the immune response subsides

  2. Fas-FasL interactions play a crucial role in killing CTL once the infection is resolved
• Emergence of memory cells

  1. Primed CD8 T cells differentiate into memory cells

  2. Memory cells undergo expansion during the initial infection, leading to an increased population of antigen-specific memory CTL

  3. Memory CTL are induced to express both Fas and FasL, contributing to their ability to respond quickly and effectively upon re-encounter with the pathogen

  4. Presence of memory CTL provides long-term immunity and protection against future infections by the same pathogen