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Effector Mechanisms of Cell-Mediated Immunity (CMI)

Cell-mediated immunity (CMI) is carried out by T lymphocytes that recognize peptide antigens displayed on MHC molecules of other cells. Unlike humoral immunity, CMI does not involve antibodies - it depends on direct cell-cell interactions and secreted cytokines. There are two broad arms: CD4+ helper T cell-mediated responses and CD8+ cytotoxic T lymphocyte (CTL)-mediated killing.

Overview: Why CMI is Needed

Certain pathogens evade humoral immunity by living inside host cells - viruses replicating in the cytosol, and bacteria such as Mycobacterium tuberculosis or Listeria that survive in phagocytic vesicles. Antibodies cannot reach these intracellular organisms. CMI evolved specifically to handle these threats by either activating phagocytes to destroy intravesicular organisms or directly killing infected cells.
  • Cellular and Molecular Immunology, p. 49-50
  • Robbins & Kumar Basic Pathology, p. ~147

Step 1: Generation of Effector T Cells

Naive T cells circulate through secondary lymphoid organs (lymph nodes, spleen, MALT). When a naive T cell encounters its cognate antigen - presented as a peptide:MHC complex on a dendritic cell - it receives two signals:
  • Signal 1: TCR engagement with peptide-MHC complex
  • Signal 2 (costimulation): CD28 on the T cell binds B7 (CD80/CD86) on the APC
This drives clonal expansion and differentiation into effector T cells, which no longer need costimulation for activation and redistribute to sites of infection in peripheral tissues. - Janeway's Immunobiology 10e, p. 368

Effector Mechanism 1: CD8+ Cytotoxic T Lymphocyte (CTL) Killing

CTLs recognize peptides presented on MHC class I molecules (expressed on virtually all nucleated cells). This allows them to survey for any cell that has been "hijacked" by an intracellular pathogen. Once a CTL recognizes its target, it kills via two distinct pathways, both culminating in apoptosis of the target cell.
CTL killing pathways - granule-dependent and Fas/FasL-dependent leading to caspase activation and apoptosis

A. Perforin/Granzyme Pathway (Granule-Dependent Killing)

This is the dominant CTL killing mechanism, especially against virally infected cells.
Perforin/granzyme pathway: cytotoxic granule exocytosis, granzyme B activating BID and caspases, granzyme A causing DNA breaks via SET complex, leading to apoptosis
Sequence of events:
  1. TCR recognition: CTL binds target cell displaying peptide-MHC I complex
  2. Immunological synapse formation: The cytoskeleton of the CTL polarizes its cytotoxic granules toward the point of contact at high speed (up to 1.2 µm/s)
  3. Directional degranulation: Cytotoxic granules (modified lysosomes) are exocytosed at the synapse - this directionality prevents killing of innocent bystander cells
  4. Perforin (a pore-forming protein similar to complement C9) oligomerizes in the target cell membrane, forming pores that permit entry of granzymes into the cytosol (or facilitates endocytosis/escape of granule contents from endosomes)
  5. Granzyme B (serine protease) cleaves and activates:
    • BID → triggers Bax/Bak pore in mitochondria → release of cytochrome c → formation of the apoptosome (with APAF-1/caspase-9) → activation of caspase-3 and caspase-7
    • Caspases 3 & 7 directly (shortcut route)
  6. Granzyme A cleaves the SET complex (ER-associated), releasing NM23-H1 nuclease into the nucleus → single-stranded DNA breaks
  7. CTL disengages ("kiss of death") and seeks another target - it is a serial killer with rapid synthesis of new granules
Perforin deficiency in humans causes type 2 familial hemophagocytic lymphohistiocytosis (FHL), a fatal disorder of immune hyperactivation. - Roitt's Essential Immunology, p. 273

B. Fas/Fas Ligand (FasL) Pathway - Death Receptor-Dependent Killing

  1. CTLs express Fas ligand (FasL/CD95L) on their surface
  2. FasL engages the trimeric Fas receptor (CD95) on the target cell
  3. Fas clustering recruits the adaptor protein FADD to its cytoplasmic tail
  4. FADD recruits and activates caspase-8 (initiator caspase)
  5. Caspase-8 then:
    • Directly activates downstream caspases (caspase-3, -7) - Type I pathway
    • Cleaves BID → cytochrome c release → apoptosome → caspase activation - Type II pathway
  6. Either route leads to rapid apoptosis of the target cell
Both killing pathways account for most CTL killing activity; TNF secreted by CTLs contributes a minor third component. - Roitt's Essential Immunology, p. 274
Key point: CTLs also secrete IFN-γ and TNF, which have direct antiviral effects and activate macrophages, respectively.

Effector Mechanism 2: CD4+ T Helper Cell-Mediated Responses

CD4+ T cells recognize antigens on MHC class II molecules (expressed on professional APCs - macrophages, dendritic cells, B cells). After priming, CD4+ effector cells differentiate into functionally distinct subsets depending on the cytokine milieu at the time of activation.

A. Th1 Cells - Macrophage Activation and Classical Inflammation

Driving cytokine: IL-12 (from macrophages/DCs) Signature cytokines secreted: IFN-γ, TNF, IL-2
Effector functions:
  1. IFN-γ is a potent macrophage activator - it upregulates MHC II expression on APCs (amplifying the T cell response) and, combined with CD40L-CD40 signaling, drives classical macrophage activation
  2. Classical activation induces macrophages to produce:
    • Reactive oxygen intermediates (superoxide, H₂O₂)
    • Reactive nitrogen intermediates (nitric oxide via iNOS)
    • Lysosomal enzymes and hydrolases → This leads to destruction of ingested intracellular microbes (e.g., M. tuberculosis, Leishmania)
  3. Th1 cytokines (especially IFN-γ) stimulate production of IgG2a antibodies (opsonizing antibodies)
  4. Sustained Th1 responses with macrophage activation → granuloma formation (e.g., in tuberculosis, sarcoidosis)
  5. Th1 cells can also directly kill some target cells by expressing FasL (inducing Fas-mediated apoptosis)
Robbins & Kumar Basic Pathology (p. 147): "Th1 cells secrete the cytokine IFN-γ, which is a potent macrophage activator. The combination of CD40- and IFN-γ-mediated activation results in 'classical' macrophage activation, leading to the induction of microbicidal substances in macrophages."

B. Th17 Cells - Neutrophilic/Monocytic Inflammation

Driving cytokines: IL-6, TGF-β, IL-23 Signature cytokines: IL-17A, IL-17F, IL-22
Effector functions:
  • IL-17 acts on stromal cells and epithelial cells to recruit neutrophils and monocytes
  • Particularly important against extracellular bacteria and fungi (e.g., Candida, Staphylococcus)
  • Involved in mucosal barrier defense
  • Implicated in inflammatory diseases (psoriasis, ankylosing spondylitis, IBD)
Robbins & Kumar Basic Pathology (p. 147): "Th17 cells recruit neutrophils and monocytes, which destroy some extracellular bacteria and fungi and are involved in certain inflammatory diseases."

C. Th2 Cells - Eosinophil Activation and Anti-Helminth Defense

Driving cytokine: IL-4, IL-33, TSLP Signature cytokines: IL-4, IL-5, IL-9, IL-13
Effector functions:
  • IL-4: Stimulates B cells to produce IgE; promotes Th2 differentiation (positive feedback)
  • IL-5: Activates and recruits eosinophils → eosinophil degranulation kills helminths (e.g., Schistosoma) too large to be phagocytosed
  • IL-13: Activates mucosal epithelial cells to secrete mucus; drives alternative macrophage activation (associated with tissue repair and fibrosis)
  • Th2 responses are anti-inflammatory relative to Th1 and underlie allergic diseases when dysregulated

D. T Follicular Helper (Tfh) Cells - B Cell Help

Tfh cells (CXCR5+, PD-1+) migrate to B cell follicles in lymphoid organs and provide help for:
  • Germinal center formation
  • Affinity maturation via somatic hypermutation (selecting highest-affinity clones)
  • Isotype class switching (via CD40L-CD40 and IL-21, IL-4)
  • Long-lived plasma cell and memory B cell generation
  • Roitt's Essential Immunology, p. 290

Effector Mechanism 3: Regulatory T Cells (Tregs) - Suppression of CMI

Tregs (CD4+, CD25+, FoxP3+) are an important negative regulatory arm:
  • Suppress excessive T cell responses
  • Use the granzyme-perforin system to kill activated NK and CTL cells
  • Modulate APC activation
  • Secrete IL-10 and TGF-β to dampen inflammation

Summary Table

Effector CellMHC RestrictionKey MechanismTarget/Purpose
CD8+ CTLMHC Class IPerforin/granzyme + Fas/FasL → apoptosisVirus-infected cells, tumor cells, intracytosolic bacteria
Th1 (CD4+)MHC Class IIIFN-γ + CD40L → classical macrophage activationIntravesicular bacteria (TB, Leishmania)
Th17 (CD4+)MHC Class IIIL-17 → neutrophil/monocyte recruitmentExtracellular bacteria, fungi
Th2 (CD4+)MHC Class IIIL-5 → eosinophil activation; IL-4 → IgEHelminths, allergy
Tfh (CD4+)MHC Class IICD40L, IL-21 → B cell helpAntibody production, affinity maturation
Tregs (CD4+)MHC Class IIIL-10, TGF-β, Granzyme-PerforinSuppress excessive responses

Clinical Correlates

  • Perforin deficiency → Familial hemophagocytic lymphohistiocytosis (FHL) - fatal immune hyperactivation
  • Defective CMI (HIV, post-transplant immunosuppression) → susceptibility to intracellular pathogens (Mycobacteria, Listeria, CMV, Pneumocystis)
  • Granuloma formation (TB, sarcoidosis, leprosy) = Th1-driven macrophage activation with failure to clear antigen
  • Delayed-type hypersensitivity (DTH) = Type IV hypersensitivity - CD4+ Th1/Th17-mediated inflammatory tissue damage (e.g., tuberculin skin test, contact dermatitis)
  • Checkpoint blockade (anti-PD-1, anti-CTLA-4) works by releasing CTLA-4/PD-1-mediated inhibition of CTLs to enhance anti-tumor CMI
Sources:
  • Cellular and Molecular Immunology (Abbas), p. 49-50
  • Roitt's Essential Immunology, p. 273-274
  • Robbins & Kumar Basic Pathology, p. 147
  • Janeway's Immunobiology 10e, p. 367-368
  • Jawetz, Melnick & Adelberg's Medical Microbiology, p. 146
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