3.2 about 24 minDeep Learning viewL3 p.8–14, 21

Antigen presentation, T-cell help and antibodies

T cells see only peptide displayed on MHC. Where a protein came from decides which MHC shows it and which T cell answers; costimulation decides whether the answer is attack or tolerance; T-cell help decides which antibody class a B cell makes.

MHC class I and class II: two routes to the surface

L3 p.12–14

A T cell cannot see a whole protein. It sees a short peptide held in the groove of an MHC molecule (in humans, an HLA molecule). The two classes sample two different places in the cell, and that is the whole logic of who gets killed and who gets helped.

Teaching schematic

MHC class I: what the cell is making

  1. Cytosolic protein (viral, tumor, self) tagged with ubiquitin
  2. Proteasome cuts it into peptides
  3. TAP pumps peptides into the ER
  4. Loaded on class I heavy chain + β₂-microglobulin
  5. Surface: read by CD8 cytotoxic T cells

On every nucleated cell and platelets, so any infected cell can be killed.

MHC class II: what the cell has taken in

  1. Class II made in the ER; invariant chain blocks the groove
  2. Travels to endosomes where engulfed protein is digested
  3. Invariant chain trimmed to CLIP
  4. HLA-DM swaps CLIP for a foreign peptide
  5. Surface: read by CD4 helper T cells

On antigen-presenting cells: dendritic cells, macrophages, B cells.

Class I shows what is being made inside the cell (proteasome → TAP → ER → MHC I with β₂-microglobulin → CD8 T cell). Class II shows what the cell has taken in (endosome; the invariant chain and then CLIP hold the groove until HLA-DM swaps in a peptide → CD4 T cell).L3 p.12–14
  • MHC class I (HLA-A, -B, -C) is on all nucleated cells and platelets. Cytosolic proteins, including viral and mutant tumor proteins, are tagged with ubiquitin and cut by the proteasome. TAP (transporter associated with antigen processing) pumps the peptides into the endoplasmic reticulum, where they load onto the class I heavy chain paired with β₂-microglobulin. CD8 binds the class I molecule, so CD8 cytotoxic T cells read it: an infected cell announces itself and is killed.
  • MHC class II (HLA-DP, -DQ, -DR) is on antigen-presenting cells: dendritic cells (including Langerhans cells of the skin), macrophages and B cells. It is assembled in the ER with the invariant chain blocking its groove, so it cannot pick up the cell's own ER peptides. In endosomes, where engulfed proteins are being digested, the invariant chain is trimmed to a fragment called CLIP, and HLA-DM exchanges CLIP for a foreign peptide. CD4 binds class II, so CD4 helper T cells read it and respond with cytokines.
L3 p.12, 14

HLA genes on chromosome 6

L3 p.12

The MHC is a cluster of genes on the short arm of chromosome 6. Each person inherits one set of linked HLA genes (a haplotype) from each parent and expresses both, so HLA genes are codominant. Because the genes are so polymorphic, two unrelated people almost never match completely, and only identical twins share the whole set.

  • Class I region: HLA-A, -B, -C.
  • Class II region: HLA-DP, -DQ, -DR.
  • Class III region: not antigen-presenting molecules but inflammatory proteins, including complement components C2, C4 and factor B, TNF and heat-shock proteins. Inherited C2 and C4 deficiencies therefore travel with HLA haplotypes, which partly explains their link with SLE (3.5, 3.7).
  • β₂-microglobulin is encoded outside the MHC (chromosome 15). In long-term dialysis it is not cleared and can deposit as Aβ₂M amyloid (3.7).
L3 p.12

Where HLA molecules are foundL3 p.12

  • I (A, B, C)

    Tissue distribution
    Every nucleated cell and platelets; not mature red cells
    Consequence
    Any infected or transplanted cell can be recognized by CD8 cells; platelets can be refractory to HLA-mismatched transfusion

  • II (DP, DQ, DR)

    Tissue distribution
    Dendritic and Langerhans cells, macrophages, B cells, thymic epithelium; induced on endothelium and other cells by IFN-γ
    Consequence
    Only these cells start CD4 responses; donor dendritic cells in a graft drive early rejection

Two signals: activation, anergy and class switching

L3 p.8, 11

Recognizing peptide on MHC is signal 1. A naive T cell also needs signal 2, costimulation: B7 molecules (CD80/CD86) on the antigen-presenting cell binding CD28 on the T cell. APCs raise B7 only after their pattern receptors have sensed microbes or damage (3.1). So a T cell is activated when its antigen arrives together with a danger signal. Signal 1 without signal 2 makes the T cell anergic, unresponsive for good: one of the peripheral tolerance mechanisms in 3.5.

Teaching schematic

T-cell activation

Signal 1 (TCR–peptide–MHC) and signal 2 (CD28–B7)1 · peptide–MHC ↔ TCR2 · B7 (CD80/86) ↔ CD28APCT cell
  • 1 + 2 → IL-2, proliferation, effector cells.
  • 1 alone → anergy (peripheral tolerance). CTLA-4 binds B7 to switch the response off.

B-cell help and class switching

  1. BCR binds antigen; B cell presents its peptide on MHC II
  2. Helper T cell recognizes it: CD40L ↔ CD40
  3. Cytokine chooses the class: IFN-γ → IgG, IL-4 → IgE, TGF-β → IgA
  4. Germinal center → plasma cells and memory B cells

No CD40L → only IgM (hyper-IgM syndrome, 3.6).

Left: T-cell activation needs TCR–peptide–MHC plus B7–CD28. Right: a B cell that presents antigen to a helper T cell receives CD40L and cytokines, which drive class switching.L3 p.11

B cells need help too. A B cell binds antigen with its receptor, internalizes it and presents its peptides on class II to a helper T cell that recognizes the same antigen. The T cell then supplies CD40 ligand (CD40L, CD154), which binds CD40 on the B cell, plus cytokines. Together these start germinal centers, affinity maturation and class (isotype) switching: the B cell keeps its antigen specificity but changes the heavy-chain constant region, and so the antibody's job.

Which cytokine chooses the classL3 p.8

  • IFN-γ (Th1)

    Switch to
    IgG (opsonizing, complement-fixing subclasses)
    Typical setting
    Bacteria and viruses; type II and III injury

  • IL-4, IL-13 (Th2)

    Switch to
    IgE
    Typical setting
    Helminths; allergy (type I)

  • TGF-β (mucosa)

    Switch to
    IgA
    Typical setting
    Gut and airway secretions, milk

In the germinal center, the helped B cell proliferates, mutates its variable genes and is selected for higher affinity. It then leaves as one of two cell types: a plasma cell, a factory with abundant rough ER and a clock-face nucleus that secretes thousands of antibody molecules per second (many home to the bone marrow and live for years), or a memory B cell that waits for the next exposure. Plasma cells no longer carry surface immunoglobulin or class II, so they no longer present antigen. A malignant clone of them makes a monoclonal protein, and its free light chains are the source of AL amyloid (3.7).

Helper subsets: Th1, Th2, Th17 and Treg

L3 p.9–10

A naive CD4 T cell becomes one of several kinds of helper, depending on the cytokines around it when it is activated. Each subset recruits a different effector, and each over-reaction gives a different disease. If you know which subset a disease uses, you know which cells you will see in the tissue.

Teaching schematic

Th1

Induced by
IL-12, IFN-γ
Master gene
T-bet
Makes
IFN-γ, IL-2
Job
Activate macrophages; help CD8; IgG
Disease
Type IV, granulomas · IL-12R defect → mycobacteria

Th2

Induced by
IL-4
Master gene
GATA3
Makes
IL-4, IL-5, IL-13
Job
IgE, eosinophils, mucus; helminths
Disease
Type I allergy, asthma

Th17

Induced by
TGF-β + IL-6 (IL-1, IL-23)
Master gene
RORγt
Makes
IL-17, IL-22
Job
Neutrophils, epithelial defense; bacteria, Candida
Disease
Psoriasis, IBD, RA · STAT3 (Job) → abscesses

Treg

Induced by
TGF-β + IL-2
Master gene
FOXP3 (CD25⁺)
Makes
IL-10, TGF-β, IL-35
Job
Suppress other T cells
Disease
FOXP3 → IPEX; CD25 → MS, T1DM
Inducing cytokines, signature products and job of each helper subset, with the disease that follows when it overreacts or fails.L3 p.9–10
  • Th1: induced by IL-12 from macrophages and dendritic cells (and IFN-γ). Makes IFN-γ and IL-2, which activate macrophages to kill intracellular microbes and help CD8 cells. Drives delayed hypersensitivity and granulomas (type IV). The lecture notes Th1 memory cells as a reservoir of HIV in latency.
  • Th2: induced by IL-4. Makes IL-4 (switch to IgE), IL-5 (eosinophils) and IL-13 (IgE, mucus). Fights helminths; drives allergy and asthma (type I).
  • Th17: induced by TGF-β with IL-6 (and IL-1, IL-23). Makes IL-17 and IL-22, which bring in neutrophils and stimulate epithelial defenses against extracellular bacteria and fungi. Overactivity drives psoriasis, IBD and rheumatoid arthritis; loss (STAT3 mutation, Job syndrome) gives staphylococcal abscesses and candidiasis (3.6).
  • Treg: induced by TGF-β with IL-2; express FOXP3 and the IL-2 receptor α chain CD25; secrete IL-10, TGF-β and IL-35 and keep other T cells in check. FOXP3 mutation causes IPEX (3.5).
  • CD8 cytotoxic T cells are activated by dendritic cells (which can show engulfed viral or tumor antigen on class I, cross-presentation) with IL-2 from CD4 helpers. Once armed, a CD8 cell kills any cell that shows the same peptide on class I: perforin opens pores, granzymes enter and activate caspases, and Fas ligand triggers the extrinsic pathway. The target dies by apoptosis, so virus is not spilled. The same killing destroys donor graft cells, β cells in type 1 diabetes and virus-infected hepatocytes in hepatitis B. See cytotoxic T-cell killing in Chapter 1.
L3 p.9–10

Immunoglobulin classes and what each one does

L3 p.8, 21

Every antibody has two identical light chains and two identical heavy chains. The variable ends bind antigen; the heavy-chain constant region decides what happens next: whether the antibody activates complement, binds phagocytes or mast cells, crosses the placenta or is secreted onto mucosa. Naive B cells start with surface IgM and IgD; class switching later swaps in another constant region.

Lecture slide

Diagram of immunoglobulin classes: monomeric IgG, IgD and IgE, dimeric secretory IgA with J chain and secretory component, and pentameric IgM with a J chain.
Lecture diagram of the five classes. IgM is a pentamer and secretory IgA a dimer, both joined by a J chain; IgG, IgD and IgE are monomers.L3 p.21

Function follows the constant regionL3 p.8, 20–21

  • IgM

    Form
    Pentamer (surface monomer on naive B cells)
    Key functions
    First antibody in a primary response; best complement activator; agglutinates
    Clinical hooks
    ABO isohemagglutinins (anti-A, anti-B) → intravascular hemolysis; cannot cross the placenta

  • IgG

    Form
    Monomer; most abundant in serum
    Key functions
    Secondary response; opsonizes (Fc receptors), fixes complement, neutralizes toxins, ADCC by NK cells; crosses the placenta
    Clinical hooks
    Newborn protection; HDN (anti-D); most type II and III injury

  • IgA

    Form
    Dimer + secretory component in secretions
    Key functions
    Mucosal neutralization; most abundant antibody produced daily; in milk
    Clinical hooks
    Selective IgA deficiency; IgA vasculitis and IgA nephropathy

  • IgE

    Form
    Monomer bound to FcεRI on mast cells and basophils
    Key functions
    Helminth defense with eosinophils; allergy
    Clinical hooks
    Type I hypersensitivity; skin-prick test

  • IgD

    Form
    Monomer on naive B cells
    Key functions
    Antigen receptor with IgM
    Clinical hooks
    —

Bridge: the Th1–macrophage axis and the granuloma

L3 p.26, 45L2 p.42–43

When a macrophage cannot destroy what it has eaten, typically Mycobacterium tuberculosis, it presents mycobacterial peptides on class II and secretes IL-12. CD4 cells become Th1 cells and release IFN-γ, which activates the macrophages; TNF holds the structure together. Activated macrophages become epithelioid cells and fuse into multinucleated giant cells, and a cuff of lymphocytes forms around them: a granuloma, the persistent form of type IV hypersensitivity. In tuberculosis its center undergoes caseous necrosis.

  1. Macrophage cannot kill mycobacteria
  2. IL-12 → naive CD4 becomes Th1
  3. IFN-γ activates macrophages
  4. Epithelioid cells, giant cells (TNF maintains)
  5. Granuloma walls off the organism
L3 p.26L2 p.42–43

Knowledge check · 3.2

Answer, read why, and try again whenever you like. Answers are kept in both study modes.

0 of 4 correct
  1. Q1Class II presentation in delayed hypersensitivityL3 p.12, 26Ch. III cases p.8

    During a physical examination, purified protein derivative from Mycobacterium tuberculosis is injected into the skin of a 22-year-old man. Three days later the site is raised and indurated.

    Which glycoprotein was directly involved in presenting antigen during the initiation phase of this delayed hypersensitivity reaction?

  2. Q2Class I pathway (TAP)L3 p.12, 14

    A herpesvirus makes a protein that blocks TAP in the cells it infects.

    What is the most likely consequence for the infected cells?

  3. Q3Class switching signalsL3 p.8, 11, 16

    A B cell specific for a dust-mite protein presents it to a Th2 cell. Which combination of signals makes the B cell switch to producing IgE?

  4. Q4Immunoglobulin classesL3 p.21

    Lecture slide

    Diagram of IgG, secretory IgA, IgD, IgE and pentameric IgM with a J chain.

    The largest antibody in the figure, a pentamer joined by a J chain, is the class that:

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