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.