NK Cells and Innate Immune Cells
Three families of innate cell ★★
TMU groups the innate immune cells three ways, and the grouping is worth learning because the third family keeps turning up as a distractor in exam questions about adaptive immunity.
| Family | Members |
|---|---|
| Classical innate immune cells | Phagocytes (monocyte/macrophage, neutrophil), dendritic cell, mast cell, basophil, eosinophil |
| Innate lymphoid cells (ILCs) | ILC1, ILC2, ILC3, and NK cells |
| Innate-like lymphocytes (ILLs) | NKT cells, γδ T cells, B1 cells |
Innate-like lymphocytes are the awkward middle ground: they are lymphocytes, with rearranged receptors, but their repertoires are so limited that they behave like innate cells — fast, stereotyped, no memory. That is why MCQ Q11 offers γδ T cells, B1 cells and NKT cells as the three wrong answers to “which participates in adaptive immunity”. All three are wrong for the same reason, and this table is that reason.
- Name the classical innate immune cells. → Phagocytes (monocyte/macrophage, neutrophil), DC, mast cell, basophil, eosinophil
- Which innate lymphoid cells are there? → ILC1, ILC2, ILC3 and NK cells
- Name the three innate-like lymphocytes. → NKT, γδ T cells, B1 cells
PRR and PAMP — how innate immunity recognises ★★★
Unit 1 said innate immunity uses pattern-recognition receptors while adaptive immunity uses TCR and BCR. This is what that actually means, and it is one of the most elegant ideas in the subject.
The receptors expressed by innate immune cells, which recognise certain molecular structures owned by pathogens.
Highly conserved specific molecular structures expressed by pathogens or their products, which are absolutely distinct from normal host substances and are recognised by the PRRs of innate immune cells.
Substances produced by or released from damaged and dying cells, also recognised by PRRs — so the same receptors report tissue injury as well as infection.
Adaptive immunity solves recognition by brute force: ten billion random receptors, one per lymphocyte. Innate immunity cannot do that — it must work immediately, with receptors already made. So it targets what pathogens cannot change: structures conserved across whole classes of microbe because they are essential to being one. Bacterial LPS, peptidoglycan, fungal mannans, double-stranded viral RNA.
A bacterium cannot abandon its cell wall to escape detection. That is why a few dozen PRRs can cover the microbial world, and why they can be encoded in the germline and inherited rather than generated afresh in every individual.
| PRR | Location | Example | Ligands |
|---|---|---|---|
| Toll-like receptor (TLR) | Plasma membrane, endosomes and lysosomes of DCs, phagocytes, B cells, endothelial cells | TLR1–9 | Bacterial LPS, peptidoglycans, viral nucleic acids |
| C-type lectin receptor | Plasma membrane of phagocytes | Mannose receptor | Carbohydrates of fungi, mycobacteria, viruses, parasites, some allergens |
| Scavenger receptor | Plasma membrane of phagocytes | CD36 | Microbial diacylglycerides |
| Pentraxin | Plasma | C-reactive protein | Microbial phosphorylcholine and phosphatidylethanolamine |
Charles Janeway Jr — the Janeway of the textbook this course cites — proposed the pattern-recognition theory and predicted that innate immunity controls adaptive immunity. Both predictions were confirmed, and the 2011 Nobel Prize in Physiology or Medicine went to Bruce Beutler and Jules Hoffmann for the discovery of the receptors themselves.
The 'innate controls adaptive' half is the part you have already been using: B7 appears on an APC only after a PRR has detected a PAMP. Signal 2 in Units 7 and 8 is Janeway's prediction in action — the innate system deciding whether the adaptive system is allowed to respond.
- Define PRR. → Receptors on innate immune cells that recognise molecular structures owned by pathogens
- Define PAMP. → Highly conserved structures on pathogens, absolutely distinct from host substances
- What is a DAMP? → A molecular pattern released from damaged or dying cells
- Name four PRR families. → Toll-like receptors, C-type lectin receptors, scavenger receptors, pentraxins
- Which PRR recognises LPS? → Toll-like receptors
- Why can a fixed set of receptors cover all pathogens? → PAMPs are conserved and essential, so pathogens cannot discard them
Neutrophils ★★
| Feature | Detail |
|---|---|
| Proportion | 50–70% of circulating leukocytes — the majority |
| Main function | Phagocytose microbes — especially opsonised microbes — and products of necrotic cells, destroying them in phagolysosomes |
| Also | Secrete granule contents and extrude nuclear contents to immobilise and kill extracellular microbes — but this may also damage healthy tissue |
| Speed | Migrate to sites of infection rapidly after microbes enter |
| Lifespan | Function for only 1–2 days, then most die |
| Clinically | The rising count (leukocytosis) is used as an indication of infection |
Two details there repay attention. First, especially opsonised microbes — this is the pay-off from Units 3 and 4. A neutrophil ingests a bare bacterium slowly and an IgG-coated or C3b-coated one efficiently, because it has FcγR and complement receptors. Second, may damage healthy tissues — extruding nuclear contents to trap bacteria is effective but indiscriminate, and much of the tissue damage in severe infection is collateral.
- What proportion of circulating leukocytes are neutrophils? → 50–70%
- How long do they function? → Only 1–2 days
- What do they preferentially phagocytose? → Opsonised microbes
- What is leukocytosis used for clinically? → As an indication of infection
Mononuclear phagocytes ★★★
The macrophage lineage runs HSC → myeloid progenitor → pre-monocyte → monocyte (bone marrow) → monocyte (blood) → macrophage (tissue). The cell that leaves the blood and settles in a tissue takes that tissue's name, and the list is examinable.
| Tissue | Name of the resident macrophage |
|---|---|
| Liver | Kupffer cells |
| Kidney glomerulus | Mesangial cells |
| Brain | Microglia |
| Lung | Alveolar macrophages |
| Connective tissue | Histiocytes |
How a macrophage recognises its target
| Receptor type | Members | Recognises |
|---|---|---|
| PRR / non-opsonic receptors | Mannose receptor (MR), scavenger receptor (SR), Toll-like receptor (TLR) | PAMPs directly — no antibody needed |
| Opsonic receptors | FcγR and C3bR / C4bR | Microbes already coated with antibody or complement |
This table is the join between innate and adaptive immunity, drawn on a single cell surface. Early in an infection the macrophage has only its PRRs — it recognises the pathogen directly, if slowly and non-specifically. Days later, once antibody exists and complement has been fixed, the opsonic receptors take over and the same macrophage becomes far more efficient at the same job.
The adaptive response does not replace the macrophage. It upgrades it — which is exactly what Unit 1 meant by saying adaptive immunity borrows innate effector mechanisms.
- Kill and remove pathogens
- Kill intracellular bacteria and target cells — tumour cells, virus-infected cells
- Participate in and stimulate inflammation
- Process and present antigens — the APC role (Unit 11)
- Immunological regulation
- Name the tissue macrophages. → Kupffer (liver), mesangial (kidney), microglia (brain), alveolar (lung), histiocyte (connective tissue)
- Name the macrophage's non-opsonic receptors. → Mannose receptor, scavenger receptor, Toll-like receptor
- Name the opsonic receptors. → FcγR and C3bR/C4bR
- List the five macrophage functions. → Kill pathogens · kill intracellular bacteria and target cells · inflammation · antigen presentation · immune regulation
How macrophages kill ★★
| System | Weapons |
|---|---|
| Oxygen-dependent | Reactive oxygen intermediates (ROIs) — O₂⁻, OH⁻, H₂O₂, ¹O₂ Reactive nitrogen intermediates (RNIs) — NO |
| Oxygen-independent | Low pH (3.5–4), lysozyme, defensins |
Children who cannot generate the respiratory burst — because NADPH oxidase is defective — have phagocytes that ingest bacteria perfectly well but cannot kill the catalase-positive ones. The organisms survive inside the phagocyte, and the body walls them off instead: hence recurrent abscesses and the granulomas that give the disease its name.
It is the clean experiment for this table. The oxygen-independent system is still intact, which is why these children are not defenceless — just selectively vulnerable to the organisms that the ROIs were needed for.
- Name the oxygen-dependent killing intermediates. → ROIs (O₂⁻, OH⁻, H₂O₂, ¹O₂) and RNIs (NO)
- Name the oxygen-independent mechanisms. → Low pH 3.5–4, lysozyme, defensins
NK cells ★★★
| Feature | Detail |
|---|---|
| Distribution | Peripheral blood, liver, lymph node, spleen |
| Antigen receptor | None — no antigen-specific receptors |
| Surface markers (human) | CD3⁻ CD19⁻ CD56⁺ CD16⁺ |
| Function | Directly kill tumour cells and virus-infected cells without antigen stimulation; can mediate ADCC |
CD3⁻ — not a T cell. CD19⁻ — not a B cell. CD56⁺ — the NK adhesion marker from Unit 6. CD16⁺ — FcγRIII, the receptor that lets it do ADCC. The four markers say, in order: not T, not B, NK, and here is how it kills antibody-coated cells.
NK cells recognise targets two ways. The first is straightforward: FcγRIII (CD16) binds antibody already coating a cell, and the NK cell kills it — that is ADCC, and it is the mechanism behind True/False Q10 in Unit 14, where NK cells are listed among the effectors of type II hypersensitivity. The second mechanism is the interesting one, and it has its own section.
- Give the NK surface marker profile. → CD3⁻ CD19⁻ CD56⁺ CD16⁺
- Do NK cells have antigen-specific receptors? → No
- What can NK cells kill, and do they need antigen stimulation? → Tumour cells and virus-infected cells; no stimulation needed
- Which receptor lets NK cells perform ADCC? → FcγRIII (CD16)
Missing self — the NK cell's logic ★★★
The lecture ends this section with a question, and it is the right one to think about: NK cells kill tumour cells and virus-infected cells, but not your own normal tissue. Why? The answer is one of the most elegant pieces of design in immunology, and it runs backwards from what you would expect.
| Killer activating receptors | Killer inhibitory receptors | |
|---|---|---|
| Members | KIR: KIR2DS, KIR3DS KLR: CD94/NKG2C, NKG2D NCR: NKp46, NKp30, NKp44 | KIR2DL, KIR3DL CD94/NKG2A |
| Bind | Non-class-I-HLA molecules | Class I HLA molecules |
Every other killer in this course asks “is this thing foreign?” The NK cell asks “is this thing still showing me proof that it is mine?” — and that proof is MHC class I.
On a normal cell, class I HLA is displayed normally, the inhibitory receptors are engaged, and their signal outweighs the activating signal. Killing is switched off.
On an abnormal cell — many tumours, and cells infected by viruses that down-regulate MHC I to hide from CTLs — class I is missing. The inhibitory signal is lost, the activating receptors (NKG2D and the NCRs) win, and the NK cell kills. This is called “missing self” recognition.
Put the NK cell next to the CD8⁺ CTL from Unit 7 and the design becomes obvious. A CTL kills a cell that displays viral peptide on MHC class I. So the smartest possible escape for a virus is to switch MHC class I off — and many, including herpesviruses and HIV, do exactly that.
But that escape is a trap. A cell with no MHC class I is invisible to CTLs and simultaneously defenceless against NK cells. The two killers are complementary: one kills cells that show the wrong thing, the other kills cells that show nothing at all. There is no MHC expression level at which a virus is safe from both.
- What do NK inhibitory receptors bind? → Class I HLA molecules
- What do activating receptors bind? → Non-class-I-HLA molecules
- On a normal cell, which signal predominates? → Inhibitory — killing is suppressed
- What is 'missing self'? → Loss of class I HLA removes inhibition, so the NK cell kills
- Name two activating receptors that act in missing-self killing. → NKG2D and the NCRs
- Why can't a virus escape both CTL and NK cells? → Losing MHC I hides it from CTLs but exposes it to NK cells
Revision layer
Where this unit is examined
No past-paper item is owned by this unit outright, but it supplies the mechanism behind two that are: MCQ Q17 (NK cells are not involved in type I hypersensitivity — Unit 13) and True/False Q10 (NK cells, macrophages and complement are involved in type II — Unit 14). Both turn on knowing that the NK cell's weapon is ADCC through CD16, which needs IgG on a target cell — present in type II, absent in type I.
The whole unit on one screen
| Question | Answer |
|---|---|
| Three innate cell families? | Classical innate cells · innate lymphoid cells (ILC) · innate-like lymphocytes (ILL) |
| Innate-like lymphocytes? | NKT · γδ T · B1 — the three wrong answers in MCQ Q11 |
| PRR / PAMP / DAMP? | Innate receptors / conserved pathogen structures / molecules from damaged cells |
| Four PRR families? | TLR · C-type lectin · scavenger · pentraxin |
| Neutrophil share and lifespan? | 50–70% of leukocytes; functions 1–2 days |
| Tissue macrophages? | Kupffer · mesangial · microglia · alveolar · histiocyte |
| Macrophage receptor types? | PRR (MR, SR, TLR) and opsonic (FcγR, C3bR/C4bR) |
| Oxygen-dependent killing? | ROIs (O₂⁻, OH⁻, H₂O₂, ¹O₂) and RNIs (NO) |
| Oxygen-independent killing? | Low pH 3.5–4, lysozyme, defensins |
| NK markers? | CD3⁻ CD19⁻ CD56⁺ CD16⁺ |
| Inhibitory receptors bind? | Class I HLA |
| Missing self? | No class I → inhibition lost → NK kills |
- Define PRR and PAMP. → Innate receptors; conserved pathogen structures distinct from host molecules
- Which cell type is 50–70% of circulating leukocytes? → Neutrophils
- Name the liver and brain macrophages. → Kupffer cells and microglia
- How does a macrophage kill without oxygen? → Low pH, lysozyme, defensins
- Give the NK marker profile. → CD3⁻ CD19⁻ CD56⁺ CD16⁺
- Why does an NK cell spare a normal cell? → Its class I HLA engages inhibitory receptors, which outweigh activation
- What is ADCC, and which NK receptor does it? → Killing an antibody-coated cell, via FcγRIII (CD16)