Cell-Mediated Immunity

Why the body needs a separate cellular arm

• Antibody works well against extracellular threats, but two categories of pathogen live inside host cells, out of antibody's reach:
  • Facultative intracellular organisms — able to survive inside the very phagocytes meant to destroy them.
  • Obligate intracellular organisms — cannot replicate at all outside a host cell.
• Cell-mediated immunity is orchestrated by the Th1 subset of helper T cells, acting through cytokine signaling rather than direct cytotoxicity.
• Two effector arms carry out the actual killing/clearance:
  Macrophages— boosted killing of ingested microbes
  CD8+ cytotoxic T cells— direct lysis of infected host cells
• NK cells contribute an innate, antigen-independent layer that overlaps mechanistically with CTLs.

Th1 licensing of macrophages (and B cells)

Two-signal priming and effector trafficking

• IL-2 is the dominant autocrine growth signal — the activated T cell makes it and expresses its own receptor, driving clonal expansion.
• Macrophage-derived IL-12, together with IFN-γ, pushes the naive Th cell to commit to the Th1 lineage.
• Once expanded, effector and memory lymphocytes exit the lymph node via efferent lymphatics, enter the blood, and traffic to the infected tissue.

Cytotoxic T lymphocytes (CD8+)

• Recognize target cells via TCR binding to peptide presented on MHC class I — present on essentially all nucleated cells.
• Normal self-peptides on healthy cells should not be recognized by any circulating CTL clone (self-tolerance).
• A cell harboring an intracellular pathogen, or expressing tumor neoantigens, presents non-self peptide on MHC I — that clone can now engage.
• Note: mismatched HLA molecules on transplanted tissue can themselves look "non-self" to CTLs even when presenting normal peptides — the basis of cellular graft rejection.
• CTLs can activate and clonally expand on MHC I signal alone, but IL-2 from Th1 cells (via cross-priming) greatly amplifies this, and local interferons upregulate MHC expression to make targets easier to detect.

Killing sequence

Three ways to induce target-cell death

• Perforin/granzyme pathway: perforin polymerizes pores in the target membrane → granzymes (serine proteases) enter → caspase cascade activated → apoptosis.
• Cytokine-mediated: IFN-γ combined with TNF-α or TNF-β can push a target into apoptosis independent of granule release.
• Fas/FasL pathway: FasL on the activated CTL engages Fas on the target → caspase activation → apoptosis.

▶ CTL killing pathways (perforin/granzyme & Fas/FasL) · @StepWiseUSMLE

NK cells — killing without prior sensitization

• Do not require antigen-specific priming; activity is instead held in check by inhibitory signals.
• Normal cells express class I MHC (via HLA-E, among others), which engages NK inhibitory receptors and prevents attack.
• Cells that downregulate MHC I — a common viral immune-evasion trick, or a feature of some tumors — lose that inhibitory signal and become NK targets ("missing self").
• Once triggered, the killing machinery is essentially the same perforin/granzyme system CTLs use.
• Th1 cytokines (IFN-γ, IL-12 signaling loop) enhance NK activity, tying this innate mechanism into the adaptive Th1 response.

Antibody-dependent cell-mediated cytotoxicity

• Mechanism that lets antibody specificity direct cells that themselves have no antigen receptor of their own.
• Effector cells carrying Fc receptors for IgG (CD16): NK cells, macrophages, neutrophils, eosinophils.

• Effector mechanisms deployed vary by cell type, but overlap heavily with CTL/NK tools: lytic enzymes, TNF, perforin/granzymes.
• The effector cell itself is not antigen-specific — specificity comes entirely from the bound antibody's idiotype.

Cellular effectors side by side