T Cells

Killer T Cells

  • Two types:
    • Cytotoxic T Lymphocytes (CTLs) or CD8+ T cells
    • Natural Killer (NK) cells (innate)

T Cell Education in the Thymus

  • Immature T cells enter the thymus.
  • Mature into either CD4+ or CD8+ cells.
  • Circulating blood T cells should be primarily CD4+ or CD8+.
  • CD4 T cells activate macrophages, induce inflammation, help B cells and CD8 T cell response.
  • Cytotoxic T cells (CTLs) lyse infected or cancer cells.

Comparison of CTLs and NK Cells

  • Similar functions but may play different roles during infection.
  • Innate response (NK cells) acts quickly (hours to days).
  • Adaptive immunity (CTLs) takes longer (days to weeks).

Viral Infection Example

  • Type 1 interferon and NK cells activate early.
  • Virus-specific CTL response starts later (day 5 or 6).
  • T cells need to recognize antigen and undergo clonal expansion, which takes time.

Why Killer Cells Are Necessary

  • CD4 T cells activate macrophages, but sometimes that's insufficient.
  • Viruses infect cells lining mucosal surfaces (epithelial cells) or hepatocytes.
  • Those cells may lack host defense mechanisms.
  • Some pathogens escape from phagosomes into the cytosol (e.g., Listeria monocytogenes).
  • In the cytosol, pathogens can survive and proliferate.
  • Killer cells work with CD4 T cells and macrophages to eliminate infection.

Roles of CD4 and CD8 T Cells

  • CD4 T cells produce cytokines and enhance macrophage killing of intracellular pathogens.
  • CD8 T cells kill infected cells (virus, intracellular bacteria, parasites) and cancer cells.

Induction of CD8 T Cells

  • Primary site: secondary lymphoid organs (lymph node or spleen).
  • Naive T cells recognize cognate peptide presented by dendritic cells.
  • T cells proliferate and differentiate.
  • T cells leave lymph nodes, circulate, and find target cells in tissues.
  • CTLs recognize endogenous peptides presented by MHC class I molecules (8-11 residues).
  • MHC class I is essential for CD8 T cell activation.

Stepwise Killing by CTLs

  • T cells primed in lymph nodes circulate and enter tissues.
  • T cells find cognate peptide in target tissue.
  • TCR on CTL recognizes peptide on target cells.
  • Multiple receptor-ligand interactions enhance interaction (ICAM, LFA-1, CD8 molecules).
  • Immunological synapse stabilizes interaction.
  • CTL releases granules, leading to target cell death.

Visualizing CTL Killing

  • Calcium dye marks viable cells (green).
  • Latex granules in CTLs are red.
  • CTLs deliver granules, and target cells lose green fluorescence, triggering apoptosis.

Mechanisms of Target Cell Elimination

  • Interaction between CTL/NK cells and target cells.
  • Two main mechanisms:
    • Granule exocytosis (perforin and granzymes)
    • Fas-Fas ligand interaction

Granule Exocytosis

  • Involves perforin and granzymes.
  • Granzymes: serine proteases (A, B, C).
  • Granzyme B activates caspases, leading to apoptosis.
  • Perforin punches holes in the membrane, allowing granzyme entry.
  • Granulysin also triggers cell death.

Fas-Fas Ligand Mechanism

  • Fas ligand on CTL binds to Fas on target cells.
  • Leads to target cell death.
  • Less significant than perforin/granzyme mechanism.

CTL Protection Mechanisms

  • CTLs deliver cytotoxic granules directly into target cells.
  • Granules contain cathepsin B, a proteolytic enzyme.
  • Cathepsin B degrades excess perforin on CTL surface.

Cytokine Production by CD8 T Cells

  • CD8 T cells produce interferon-gamma and TNF.
  • CD8 T cells can activate infected macrophages through interferon-gamma production.

Natural Killer (NK) Cells

  • Innate cells that function without prior differentiation.
  • Circulate in blood and reside in tissues.
  • Blood-derived cells with lymphoid morphology.
  • Lyse infected cells, similar to CTLs.
  • Recognize targets differently (germline-encoded receptors).
  • Recognize stressed or damaged host cells and virally infected cells.

NK Cell Activation

  • Blocked when recognizing healthy cells.
  • Activated when recognizing infected or damaged cells.
  • Receptors divided into activating and inhibiting types.
  • Balance between activating and inhibiting signals determines killing.

Inhibitory Receptors

  • Bind to MHC class I molecules.
  • Deliver negative signaling, preventing NK cell activation.
  • Most cells express MHC class I, so NK cells are usually not activated.

Missing Self Hypothesis

  • Cancer or viral infection can inhibit MHC class I expression.
  • Lack of MHC class I leads to lack of inhibitory signaling.
  • Activating signals dominate, and NK cells kill the target cells.

Stress-Induced Activation

  • Normal MHC expression, but strong activating signals due to cell stress.
  • Caused by infection, DNA misfolding, or abnormal processes.
  • Activating signals dominate inhibitory signals.
  • NK cells lyse MHC class I negative cells and CTLs avoid killing.

Cytokine Production by NK Cells

  • NK cells produce interferon-gamma.
  • Interferon-gamma activates macrophages and contributes to intracellular pathogen control.
  • NK cells utilize perforin and granzyme for killing.

Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

  • Unique to NK cells.
  • NK cells bind to antibody-coated cells through Fc receptors.
  • IgG antibody binds to antigen on infected/cancer cells.
  • Fc region of IgG binds to Fc-gamma receptor III (CD16) on NK cells.
  • Binding activates NK cells to produce cytokines and kill infected cells.

Key Points

  • Killer cells: innate (NK) and adaptive (CD8 T cells).
  • Utilize perforin and granzyme for killing.
  • Different requirements for CD8 T cell and NK cell activation.
  • MHC class I molecules play different roles in activation.
  • Both cell types control viral infections, intracellular bacteria/parasites, and cancer.