Immunology: Chapter 8 — T-cell development and cell-mediated immunity

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8.1 The thymus #

8.1.1 Positive selection, negative selection, and AIRE #

T-cell precursors use the same RAG enzymes and 12/23 rule as B cells. β rearranges first and is tested with pre-Tα; success excludes the other β allele, makes the cell double positive for CD4 and CD8, and allows α to rearrange. There is no somatic hypermutation, so the thymus’s decision is permanent. Positive selection is on cortical thymic epithelial cells: weak binding to self peptide in self MHC lets the cell live, and no binding is death by neglect. Negative selection deletes cells that bind self peptide–MHC strongly, especially on medullary epithelium and dendritic cells. AIRE in medullary epithelium drives tissue-restricted genes, insulin among them, so peptides from organs the thymus does not build are still displayed. Loss of AIRE causes APS-1 (APECED), autoimmunity against several endocrine organs. Some strong binders are diverted into Foxp3-positive regulatory T cells rather than deleted.

8.1.2 CD4 versus CD8, and the cells that die #

A cell selected on class II keeps CD4, with ThPOK enforcing the choice; a cell selected on class I keeps CD8, with Runx3. The co-receptor that matched the selecting MHC is the one kept. More than 95 per cent of thymocytes never leave. Most die of neglect, and a further fraction is deleted. The emigrants recognise self MHC, are not strongly reactive to the self peptides the thymus could show, and are naive.

8.2 Activation #

8.2.1 Three signals #

Signal 1 is the T-cell receptor on peptide–MHC. CD4 or CD8 brings Lck to the ITAMs of CD3 and ζ; ZAP-70 then assembles the pathways to NFAT, NF-κB, and AP-1, and those factors drive IL-2. Signal 2 is CD28 binding CD80 or CD86, the B7 molecules that rise when a dendritic cell has sensed a PAMP or a DAMP. Later, CTLA-4 binds B7 more tightly than CD28 and inhibits, and PD-1 inhibits when it meets PD-L1. ICOS supports follicular helpers, and CD40 ligand on the T cell feeds back onto the dendritic cell or the B cell. Signal 3 is the cytokine that chooses the subset: IL-12 towards Th1 and CD8 effectors, IL-4 towards Th2, IL-6 with other inflammatory cytokines towards Th17, and TGF-β with IL-2 towards a peripheral regulatory cell. IL-2, made after signals 1 and 2, is the clone’s growth factor through the high-affinity receptor that includes CD25. Regulatory T cells express CD25 from the start and depend on IL-2 made by others.

8.2.2 Anergy, and recognition that ignores the peptide #

Signal 1 without signal 2 does not cause proliferation. The naive cell becomes anergic and makes IL-2 poorly even if a proper dendritic cell later shows the same peptide. Healthy tissues display self peptide without B7, and anergy is one reason that display does not start immunity. A tumour that presents antigen without costimulation can be ignored for the same reason. Superantigens break the geometry. Staphylococcal toxic-shock toxin binds MHC class II outside the groove and a Vβ domain shared by many receptors, so several per cent of T cells can fire at once. The cytokine burst is Chapter 9.

8.3 Effectors, memory, and regulation #

8.3.1 Helper subsets #

Through IFN-γ and CD40 ligand, Th1 cells make macrophages run the oxidase and fuse phagosomes to lysosomes; if the microbe persists, the result is a granuloma. Th2 cells drive the IgE, eosinophil, and mucus programme used against helminths and in asthma. Th17 cells recruit neutrophils and induce epithelial antimicrobial peptides. People who cannot make IL-17 handle extracellular bacteria and fungi at barriers poorly; Microbiology names the organisms.

8.3.2 How a CD8 cell kills #

A naive CD8 cell primed with signals 1 and 2, IL-2, and often CD4 help becomes a cytotoxic lymphocyte. It recognises the same peptide on the target’s class I and aims granules at the point of contact, sparing neighbours. Perforin pores the target membrane and admits granzymes. Granzyme B starts apoptosis through caspases and through BID and the mitochondrion. Fas ligand binds Fas and starts the extrinsic pathway through caspase-8. Either route kills by apoptosis, so the corpse is phagocytosed rather than ruptured and a cytosolic pathogen is not spilled. The killer can detach and kill again. It also secretes IFN-γ and TNF.

8.3.3 Memory and regulatory T cells #

Memory is a change in quality as well as number. Central memory cells express CCR7 and L-selectin, patrol lymphoid organs, and proliferate well on restimulation. Effector memory cells lack CCR7, enter tissues, and act quickly. IL-7 and IL-15 maintain them without a requirement for continued antigen. Regulatory T cells are the peripheral brake. Thymic ones leave already expressing Foxp3; others are induced from naive CD4 cells by TGF-β and IL-2. They suppress by IL-10 and TGF-β, by consuming IL-2 through CD25, by CTLA-4-dependent removal of B7, and by contact. Loss of Foxp3 causes IPEX, early multi-organ autoimmunity, which shows that thymic deletion alone is not enough.

8.4 Key terms, summary, and self-check #

Key terms. Positive selection; negative selection; AIRE; ThPOK; CD28; B7; anergy; superantigen; Th1; Th2; Th17; Tfh; Treg; Foxp3; perforin; granzyme; Fas ligand; central memory.

Summary. Thymocytes live if they recognise self MHC weakly and die if they recognise it strongly; AIRE lets the medulla display tissue antigens during that test. CD4 and CD8 follow the MHC class that selected the cell. Priming needs peptide, B7–CD28, and a polarising cytokine; peptide alone anergises. Helper subsets are marked by IFN-γ, IL-4, IL-17, IL-21, and IL-10 with TGF-β. CD8 cells kill by perforin and granzymes and by Fas ligand, through apoptosis. Memory cells are easier to trigger; regulatory cells restrain clones that escaped the thymus.

Self-check.

1. What does positive selection keep, what does negative selection remove, and why do most thymocytes die?

2. What is AIRE doing in the thymus, and which syndrome follows its loss?

3. What are signals 1, 2, and 3, and what happens if a naive T cell receives only signal 1?

4. Give the signature cytokine of Th1, Th2, Th17, Tfh, and Treg, and one response each steers.

5. Name two molecular routes of CD8 killing. Why does the target not spill its cytoplasm?

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