Cell-Mediated Immunity

The Th1 subset of helper T cells is the central driver of cell-mediated immunity. It directs the activation of macrophages, CD8⁺ cytotoxic T lymphocytes (CTLs), and natural killer (NK) cells. The main polarising cytokines are IL-12 (from macrophages/dendritic cells) and IFN-γ (from T cells and NK cells), which together promote Th1 differentiation and amplify the response.

Two major goals: (1) activate infected macrophages to kill ingested pathogens, and (2) generate CTLs that recognise and eliminate infected cells presenting foreign peptides on MHC class I.

Macrophages are both antigen-presenting cells and effector cells. In the context of cell-mediated immunity, classical (M1) activation by IFN-γ enhances their microbicidal capacity: increased production of nitric oxide, reactive oxygen intermediates, and TNF-α. They also upregulate MHC class II and co-stimulatory molecules, enabling them to present antigen to naïve Th cells.

Macrophage effector functions

B-cell collaboration: IFN-γ from Th1 cells induces class switching to IgG subclasses (especially IgG1 and IgG3 in humans) that opsonise pathogens, facilitating macrophage phagocytosis via Fc receptors.

CTLs recognise MHC class I–peptide complexes on target cells. Because MHC class I presents endogenous (cytosolic) peptides, any cell displaying non-self peptides (viral, tumour, or allogeneic MHC) becomes a target.

Activation and help

While CTLs can be primed by dendritic cells via cross-presentation, optimal expansion requires IL-2 from Th1 cells. IFN-γ and other inflammatory signals also upregulate MHC class I on target cells, making them more susceptible to lysis.

Mechanisms of target killing

• Perforin/granzyme pathway: Perforin forms pores in the target cell membrane; granzymes (serine proteases) enter and activate caspases → apoptosis.
• Fas–FasL interaction: CTL surface FasL binds Fas on target; downstream caspase activation leads to cell death.
• Cytokine-mediated killing: IFN-γ and TNF-α/β can also induce apoptosis in sensitive cells.

Natural killer (NK) cells are innate lymphocytes that provide rapid cytotoxicity without prior sensitisation. Their activity is regulated by a balance of activating and inhibitory receptors: inhibitory receptors recognise MHC class I (via HLA-E), so loss of MHC class I (common in viral infection or tumour) triggers NK killing.

Effector mechanisms: perforin/granzyme, FasL, and cytokine release (IFN-γ, TNF-α).

Antibody-dependent cell-mediated cytotoxicity (ADCC)

ADCC bridges humoral and cellular immunity. NK cells, macrophages, neutrophils, and eosinophils express CD16 (FcγRIII). When IgG antibodies coat a target cell (e.g., virus-infected cell or tumour), the Fc region is recognised by CD16, triggering cytotoxic granule release and target lysis. The specificity is provided by the antibody, not the effector cell.

Naïve T cells are activated in secondary lymphoid organs (lymph nodes, spleen) after encountering antigen presented by dendritic cells or macrophages. The primary growth factor for T cells is IL-2, which acts in an autocrine and paracrine manner to drive clonal proliferation.

Effector lymphocytes leave the lymphoid tissue via efferent lymphatics and blood, homing to peripheral sites of infection. Memory cells provide long-lived protection and can be rapidly reactivated upon re-exposure.

Delayed-type hypersensitivity (DTH): The same Th1/macrophage/CTL mechanisms underlie DTH reactions (e.g., tuberculin skin test, contact dermatitis to poison ivy). This is a normal protective response but can cause tissue damage if dysregulated.

• IL-2 is the main T-cell growth factor; it is the target of immunosuppressive drugs (e.g., cyclosporine, tacrolimus) and used in cancer immunotherapy (high-dose IL-2).
• IFN-γ activates macrophages and enhances MHC expression; deficiency leads to susceptibility to intracellular bacteria (e.g., mycobacteria, salmonella).
• Perforin/granzyme deficiency (e.g., familial haemophagocytic lymphohistiocytosis) results in defective CTL and NK killing.
• Fas/FasL mutations cause autoimmune lymphoproliferative syndrome (ALPS) with defective apoptosis of lymphocytes.
• NK cells are part of the innate response, but their activity is enhanced by Th1 cytokines. They are critical early defence against viruses and tumours.
• ADCC is exploited therapeutically; monoclonal antibodies (e.g., rituximab, trastuzumab) rely on FcγRIII engagement for part of their efficacy.