Lecture 10 - T cell activation

• Initiation of T cell activation

  1. T cell activation is initiated by the interaction of the TCR with peptide-MHC on antigen presenting cells (APCs)

  2. This interaction provides the first signal known as signal one, for T cell activation
• Signal one


  The TCR binding to peptide-MHC complex provides the first signal for T cell activation
• Signal one alone is not sufficient for efficient activation of naive T cells
• Signal two

  The binding of CD28 on T cells to costimulatory molecules CD80 or CD86 on APCs provides the second signal for T cell activation
• Both signal one and signal two are required for efficient activation of naive T cells
• Anergic state


  • If a naive T cell receives only signal one, it becomes anergic and does not get activated
  • Anergic T cells are unable to initiate a productive response even when their antigen is encountered in the presence of full costimulation
• The two-signal activation model helps in setting threshold limits for T cell activation, ensuring that T cells are not inappropriately activated
• Two-signal activation model

  • It plays a crucial role in safeguarding against inappropriate CD8+ T cell activation and controlling autoreactive activity
  • It leads to the production of specialised regulatory t cells that suppress autoreactive activity
• Immunological synapse


  The two-signal activation model initiates the construction of the immunological synapse, which brings together molecules that initiate TCR signalling and excludes molecules that prevent signalling via the TCR
• Negative costimulatory molecules


  • Such as CTLA-4 and PD-1, which act as 'off switches' to prevent damage to the host by switching off activated T cells
• Cellular changes required for T cell activation

  1. Reorganisation of the cytoskeleton to form the immunological synapse

  2. Concentration of key molecules at the central 'cap' of the immunological synapse

  3. Formation of supramolecular activation clusters (SMACs) within the immunological synapse

  4. Phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the CD3 complex

  5. Recruitment of kinases to the T cell receptor (TcR) via the CD3zeta (CD3z) chain

  6. Activation of phosphoinositol kinase (PI3K) activity linked to CD28
• Role of IL-2 in T cell activation

  • IL-2 is the major goal of TcR signaling and is essential for the growth and survival of naive T cells
  • Naive T cells require IL-2 for proliferation and survival
  • IL-2 production is induced by the sum of all activations in T cell signaling
  • IL-2 receptors, including high affinity (CD25) and low affinity (CD122 and CD132), are crucial for IL-2 signaling
  • CD8+ T cells require IL-2 from CD4+ T cells for expansion and activation
  • IL-2 is also necessary for the differentiation of activated CD8+ T cells to cytotoxic killer T cells
  • IL-2 signals contribute to the negative costimulatory molecules and the immunological synapse in T cell activation
• Mutations in CTLA-4, a negative regulator of T cell activation, are linked to several autoimmune conditions affecting various tissues, highlighting the importance of proper T cell activation and regulation in immune function and disease prevention
• Negative Co-stimulatory Molecules


  • CTLA-4 (cytotoxic lymphocyte antigen-4) and PD-1 (programmed death protein-1) are the two main negative co-stimulatory molecules for T cells
  • These molecules act as "off switches" for activated T cells to prevent damage to the host
• CTLA-4


  • CTLA-4 is pre-formed and stored in intracellular vesicles, and it traffics to the cell surface approximately 96 hours post-activation
  • It interacts with CD80 or CD86 to inhibit signal two required for T cell activation
  • Mutations in CTLA-4 are linked to several autoimmune conditions affecting various tissues in the body
• Mechanism of action - CTLA-4

  1. CTLA-4 outcompetes CD28 for binding to CD80/86, thereby "switching off" activated T cells via phosphatase activity

  2. It can bind to phosphatases such as PP2A and SHP2, leading to dephosphorylation of kinases on CD3 and disrupting TCR signalling
• PD-1


  • PD-1 binds to its PDL-1 and PDL-2 on APCs and tissue stroma
  • Certain tumours exploit the PD-1/PDL-1 pathway to impede CD8+ T cell responses, and immunotherapy with antibodies blocking this interaction can re-ignite the CD8+ T cells to kill the tumour
• Negative co-stimulatory molecules play a crucial role in regulating T cell responses by preventing overactivation and potential damage to the host