ImmunologyTier 2Medical Sciences concept

NK cell and cytotoxic T cell killing mechanisms (perforin/granzyme, Fas-FasL)

Core concept

	CD8 cytotoxic T cell	NK cell
Recognition	TCR sees peptide + MHC class I - antigen-specific, clonal	Balance of activating and inhibitory receptors - no antigen specificity
Needs priming?	Yes - days	No - immediate, innate
Killed target	Presents foreign peptide on MHC I	Lacks MHC I ("missing self") or is stressed
Marker	CD3+ CD8+	CD3- CD56+ CD16+

"Missing self" is the failsafe: viruses and tumours downregulate MHC class I to escape CD8 T cells - which removes the inhibitory signal and makes them NK targets
- Hence herpesviruses also encode MHC class I decoys to fool NK cells - an arms race the exam likes
NK inhibitory receptors: KIRs (human), NKG2A/CD94 binding HLA-C and HLA-E
NK activating triggers
- Loss of inhibitory (MHC I) engagement
- Activating receptors - NKG2D binding stress ligands MICA/MICB and ULBPs, NCRs (NKp30/44/46)
- CD16 (FcgammaRIII) bound by IgG on a coated target -> ADCC
- Cytokines - IFN-alpha/beta, IL-12, IL-15, IL-18

Killing mechanisms - both cells use the same two

1. Granule exocytosis (perforin/granzyme) - the dominant, fast pathway
- Immunological synapse forms, granules polarise
- Perforin polymerises a pore in a Ca2+-dependent manner, and mediates granzyme delivery
- Granzyme B activates caspase-3 and cleaves Bid -> mitochondrial apoptosis; granzyme A caspase-independent
- Granulysin (in humans) is directly antimicrobial and is the key effector in TEN keratinocyte death
2. Fas-FasL (death receptor) - slower, and the pathway of immune homeostasis
- FasL on the killer engages Fas (CD95) on the target -> FADD -> caspase-8 -> apoptosis
- Also eliminates activated lymphocytes at the end of a response - activation-induced cell death
- *ALPS (autoimmune lymphoproliferative syndrome) - FAS/FASLG/CASP10 mutation -> lymphadenopathy, splenomegaly, autoimmune cytopenias, raised double-negative (CD3+ CD4- CD8- TCRalphabeta+) T cells*, high vitamin B12 and sFasL, lymphoma risk
The killer is not harmed - cathepsin B and serpin protection; a single CTL kills serially
TNF-alpha/TNFR1 is a third, minor route

When the pathway fails

Familial haemophagocytic lymphohistiocytosis (HLH) - PRF1 (perforin), UNC13D/Munc13-4, STX11, STXBP2 - granule formation or exocytosis fails
- -> the target cell is engaged but never killed -> persistent antigen -> unrelenting IFN-gamma and macrophage activation
- Fever, cytopenias, splenomegaly, very high ferritin, high triglycerides, low fibrinogen, high soluble CD25, low/absent NK function, haemophagocytosis
- Chediak-Higashi (LYST), Griscelli (RAB27A), Hermansky-Pudlak type 2 - giant granules / albinism plus HLH
X-linked lymphoproliferative syndrome (SH2D1A/SAP) - fulminant EBV infection, dysgammaglobulinaemia, lymphoma

ADCC is how many therapeutic antibodies actually work
- Rituximab (CD20), trastuzumab (HER2), daratumumab (CD38), obinutuzumab (glycoengineered for enhanced ADCC) - IgG1 Fc recruits NK CD16
- This is why an IgG4 or Fc-silenced antibody is chosen when killing is not wanted (checkpoint inhibitors)
NK cells are the first-line defence against herpesviruses - isolated NK deficiency presents with severe or disseminated CMV, EBV, VZV and HSV, and with HPV-driven warts
Haploidentical transplant and KIR mismatch - donor NK cells that do not see a matching inhibitory HLA ligand exert a graft-versus-leukaemia effect without as much GVHD
CAR-T and CAR-NK cells kill by the same perforin/granzyme machinery, redirected by a synthetic receptor
Checkpoint blockade releases CD8 effector function; TIGIT and NKG2A blockade target the NK equivalent
Secondary HLH triggered by EBV, other infection, lymphoma, or rheumatological disease (macrophage activation syndrome in Still's/sJIA) - treat the trigger plus etoposide/steroid, anakinra, or emapalumab (anti-IFN-gamma)
Granulysin and Fas-FasL mediate the keratinocyte apoptosis of SJS/TEN - the reason it is a CD8 disease and not an IgE one

3 more sections, plus exam facts

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