IMM: BLOCK 2: LECTURE 8: T-CELL ACTIVATION AND EFFECTOR FUNCTION

T Cell Anergy

• T cells become anergic when they are unable to respond to their specific antigen.
• Anergy is a state of non-responsiveness.

Naive T Cell Activation

• Activation of naive T cells by antigen is driven by the cytokine interleukin-2 (IL-2).
• Naive and activated T cells express different forms of the IL-2 receptor.
• The IL-2 receptor is composed of alpha, beta, and gamma chains, separate from the TCR.

Naive CD4 T Cell Differentiation

• Activation of naive CD4 T cells creates five types of effector CD4 T cells.
• The cytokine environment determines the differentiation pathway a naive T cell takes.

Effector CD4 T Cell Subtypes

• TH1 Cells - induce macrophage activation making macrophages microbicidal.
• TH2 Cells - have an anti-inflammatory phenotype.
• TFH (Follicular Helper) Cells - recognize different epitopes of the same antigen as naive B cells.
• Treg Cells - limit the activities of effector CD4 and CD8 T cells.
• TH17 Cells - promote inflammation and are thought to play a role in autoimmune diseases.

Naive CD8 T Cell Activation

• Naive CD8 T cells require stronger activation than naive CD4 T cells.
• Naive CD8 T cells can be activated directly by a virus-infected dendritic cell.
• Naive CD8 T cells can be activated indirectly by a dendritic cell with insufficient co-stimulation, helped by CD4 effector T cells.
• IL-2 secreted by CD4 T cells can act directly on naive CD8 T cells interacting with the same dendritic cell.

CD8 T Cell Co-stimulation

• Some CD8+ T cells lack CD28.
• CD58 acts as a backup for co-stimulation by binding to CD2.

Effector T Cell Functions

• Effector CD8 T cells and effector CD4 TH1, TH2, and TH17 cells work at sites of infection.
• The integrin VLA-4 enables effector T cells to home to inflamed tissue.
• Effector T cell functions are mediated by cytokines and cytotoxins.

Cytotoxic CD8 T Cell Activity

• Cytotoxic CD8 T cells are selective and serial killers of infected target cells.
• Cytotoxic CD8 T cells kill target cells by inducing apoptosis.

Memory T Cells

• Some CD4+ T cells enter a memory state.
• Memory T cells express CD28, increase some adhesion molecules, but decrease surface expression of L-selectin.
• Memory CD8+ T cells can also form.

Immunological Synapse

• The immunological synapse is formed by T-cell and antigen-presenting cell (APC) interactions.

T-Cell Signal Transduction

• T-cell signal transduction is the process by which T cells receive and respond to signals from the environment.
• This process involves various signaling molecules, including the T-cell receptor (TCR) complex, co-receptors, and co-stimulatory receptors.

Importance of IL-2

• IL-2 plays a crucial role in T cell activation, proliferation, and differentiation.
• IL-2 is a growth factor that promotes the expansion of activated T cells, allowing them to mount a robust immune response.

Co-Stimulatory Molecules

• Co-stimulatory molecules are critical for T cell activation and ensure that T cells only respond to antigens presented in the context of an immune response (e.g., infection).
• CD28 is a major co-stimulatory receptor that binds to CD80 and CD86 on APCs.
• CD58 is a backup co-stimulatory molecule that can bind to CD2 on T cells.

Immunological Synapse

• The purpose of the immunological synapse is to facilitate communication and interaction between T cells and antigen-presenting cells (APCs).

T-Cell Signal Transduction

• T-cell signal transduction is the process of transmitting signals from the cell surface to the inside of the cell.
• ITAMs are signaling motifs that play a significant role in T-cell signaling.
• Specific signals are needed to activate T cells and initiate their functions.
• Different signals can trigger anergy (a state of non-responsiveness) or effector function.

IL-2 Importance

• IL-2 is a cytokine crucial for the proliferation and differentiation of activated naive T cells.
• Naive T cells and activated T cells express different forms of the IL-2 receptor.

CD4+ & CD8+ Maturation

• CD4+ and CD8+ T cell maturation differ in their activation pathways and roles in the immune response.

CD4+ Subtypes

• There are five subtypes of CD4+ T cells:
  • TH1 cells induce macrophage activation.
  • TH2 cells have an anti-inflammatory phenotype.
  • TH17 cells promote inflammation.
  • Treg cells suppress autoreactive T cells.
  • TFH cells help B cells produce antibodies.

Co-stimulatory Molecules and Signals

• Co-stimulatory molecules provide secondary signals necessary for T-cell activation.
• CD28 is a significant co-stimulatory molecule.
• CD58 acts as a back-up co-stimulatory molecule that binds with CD2.

Memory T Cells

• Some CD4+ T cells enter a memory state.
• Memory T cells express increased CD28 and decreased L-selectin.
• Memory T cells are more likely to respond rapidly to CD80/86 displayed by APCs.
• Memory T cells home to sites of inflammation rather than lymph nodes.

CD8+ Memory Cells

• CD8+ T cells can also form memory cells.
• The expression of CD58 is increased in memory T cell connections.

T Cell Killing

• T cell killing involves a process of granular exocytosis that releases cytotoxic molecules, such as perforin and granzymes.
• The release of these molecules leads to apoptosis (programmed cell death) of the target cell.
• Cytotoxic CD8 T cells can kill multiple infected target cells in succession.
• Effector T cells utilize integrin VLA-4 to home to inflamed tissues.
• Co-stimulatory signals are crucial for the activation of naive T cells but not for activating effector T cells.