ImmunologyTier 2Medical Sciences concept

Cell-mediated immunity against intracellular pathogens (T cells, macrophages, NK cells)

Core concept

Antibody cannot reach an intracellular pathogen - so the host either kills the infected cell or activates the cell to kill what is inside it
Two distinct strategies, chosen by where the organism hides
- *Cytosolic (viruses, Listeria, Rickettsia) -> antigen enters the proteasome -> MHC class I -> CD8 cytotoxic T cell kills the infected cell*
- *Vesicular / phagosomal (mycobacteria, Salmonella, Legionella, Leishmania, fungi) -> MHC class II -> CD4 Th1 -> IFN-gamma -> MACROPHAGE ACTIVATION*, killing the organism in situ
NK cells cover the gap before T cells are primed (days), and kill cells that have downregulated MHC class I to escape CD8 recognition - "missing self"
Type I interferons (IFN-alpha/beta) are the immediate antiviral layer
- Induce an antiviral state in all nucleated cells (PKR, OAS/RNase L, Mx)
- Upregulate MHC class I and antigen presentation
- Activate NK cells, dendritic cells and macrophages

Key detail

The macrophage-activation loop - the exam's core mechanism

Infected macrophage -> IL-12 (and IL-18)
-> naive CD4 -> Th1 (T-bet)
-> IFN-gamma + CD40L-CD40 contact
-> macrophage upregulates iNOS (NO), NADPH oxidase (ROS), phagolysosomal fusion, antimicrobial peptides, MHC II
-> intracellular killing; failure to kill -> granuloma (epithelioid macrophages, Langhans giant cells, T-cell cuff, +/- caseation), walling off what cannot be sterilised
TNF-alpha maintains granuloma integrity
- -> *anti-TNF therapy causes reactivation TB, histoplasmosis and listeriosis* - the clinical proof

When the loop breaks

Defect	Consequence
IL-12/IL-12R, IFN-gammaR, STAT1, TYK2 (MSMD)	Disseminated BCG and non-tuberculous mycobacteria, salmonellosis
Anti-IFN-gamma autoantibodies (adult, often South-East Asian ancestry)	Acquired phenocopy - disseminated NTM, severe salmonella, VZV
CD40L (hyper-IgM)	PJP, cryptosporidium - because DC/macrophage licensing fails
NADPH oxidase (CGD)	Catalase-positive organisms survive the phagosome
HIV/low CD4, calcineurin inhibitors, steroids, anti-TNF	Reactivation TB, PJP, CMV, cryptococcus, toxoplasma

Immune evasion strategies worth knowing

MHC class I downregulation - CMV (US2-11), HSV (ICP47 blocks TAP), HIV Nef, many tumours -> then countered by NK cells, so viruses also encode MHC decoys (CMV UL18)
Blocking phagolysosome fusion - M. tuberculosis, Legionella
Escape into the cytosol - Listeria (listeriolysin O), Shigella
Latency with minimal protein expression - herpesviruses, TB
Antigenic variation - HIV, influenza, trypanosomes

Clinical relevance

The tuberculin skin test and IGRA measure exactly this pathway - a type IV delayed hypersensitivity readout of Th1 memory
- Both are falsely negative in anergy - overwhelming TB, HIV with low CD4, malnutrition, sarcoidosis, steroids, recent live viral vaccine, acute measles
- IGRA is unaffected by BCG and by most non-tuberculous mycobacteria - the reason it is preferred in BCG-vaccinated adults
Screen for latent TB before: anti-TNF, JAK inhibitors, transplantation, high-dose steroids, anti-IL-6, and before starting dialysis
Live vaccines require intact cell-mediated immunity - contraindicated in significant T-cell deficiency, HIV with CD4 <200, high-dose immunosuppression, and pregnancy
CMV in transplant and HIV - CD8 T-cell control; monitor by quantitative PCR; letermovir prophylaxis and pre-emptive valganciclovir; CMV-specific T-cell therapy for refractory disease
Interferon as a drug - IFN-alpha historically in hepatitis B/C, hairy cell leukaemia and myeloproliferative disease (peg-IFN still used in polycythaemia vera and essential thrombocythaemia); IFN-gamma in CGD; IFN-beta in MS acts by immunomodulation rather than antiviral effect
*Checkpoint inhibitors can unmask latent TB and cause a paradoxical granulomatous (sarcoid-like) reaction* - restored Th1 function, not disease progression
Immune reconstitution inflammatory syndrome (IRIS) - restoring CD4 counts on ART regenerates the Th1 response to a previously unopposed organism (TB, cryptococcus, MAC) -> paradoxical worsening

Correlations

NK cell and cytotoxic T cell killing mechanisms
T-helper subset pathways; interleukin functions
MHC/HLA function in antigen presentation
Tuberculosis - latent infection screening and reactivation
Infection patterns by immunodeficiency type
Sarcoidosis and granulomatous disease
HIV; opportunistic infection; IRIS

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