Unit 4: Major histocompatibility complex; T and B lymphocytes

Adaptive immunity depends on lymphocytes recognising antigen through clonally distributed receptors, and on a set of surface glycoproteins—the MHC—that display peptide fragments so that T cells can survey the internal and external protein content of cells. This unit connects the display molecules (MHC), the receptors that read them (TCR, BCR) and the developmental programmes (maturation and selection) that build a functional, self-tolerant repertoire.

• Central rule of T-cell recognition: T cells recognise antigen only as a peptide bound to a self-MHC molecule—termed MHC restriction.
• Two arms of recognition: B cells (via antibody/BCR) bind native, intact antigen; T cells (via TCR) bind processed peptide–MHC.
• Genetic locus: In humans the MHC is the HLA complex on chromosome 6p21; in mice it is the H-2 complex on chromosome 17.
• Polygeny and polymorphism: Several MHC genes exist per individual, and each is highly polymorphic across the population—the most polymorphic loci known.
• Codominant expression: Both maternal and paternal alleles are expressed, maximising the range of peptides presentable.

II. The Major Histocompatibility Complex

Structure, classes and the display of processed antigen

A. Introduction of MHC

The MHC is a cluster of tightly linked genes encoding peptide-presenting glycoproteins and related immune molecules.

• Origin of name: Identified as the loci controlling rejection of transplanted tissue ("histocompatibility"); the strong loci form the major complex.
• Function: Bind short peptides and present them at the cell surface for inspection by T-cell receptors.
• Haplotype: The set of MHC alleles inherited together on one chromosome; a child shares one haplotype with each parent.
• Peptide-binding groove: A cleft formed by two α-helices resting on a β-pleated sheet floor, where the antigenic peptide sits.

B. Types of MHC

MHC genes fall into three classes distinguished by structure, ligand and function.

1. Class I (HLA-A, -B, -C):
   • Chains: One transmembrane α (heavy) chain with three domains (α1, α2, α3) non-covalently linked to β2-microglobulin (encoded outside the MHC).
   • Groove: Closed at both ends; binds short peptides of 8–10 residues.
   • Ligand for: CD8⁺ cytotoxic T cells (α3 domain binds CD8).
2. Class II (HLA-DP, -DQ, -DR):
   • Chains: Two membrane-anchored chains, α and β, each with two domains (α1α2, β1β2).
   • Groove: Open-ended; binds longer peptides of 13–25 residues.
   • Ligand for: CD4⁺ helper T cells (β2 domain binds CD4).
   • Class III: Not peptide-presenting; encodes secreted immune proteins such as complement C4, C2, factor B and TNF.

C. Cellular distribution of MHC molecules

Expression pattern matches each class's surveillance role.

• Class I—near-universal: Expressed on essentially all nucleated cells and platelets, letting cytotoxic T cells check any cell for intracellular (viral, tumour) proteins.
  • Exceptions: Mature red blood cells lack it; neurons and cornea express little.
• Class II—restricted to APCs: Confined to professional antigen-presenting cells—dendritic cells, macrophages and B cells—plus thymic epithelium.
• Regulation: IFN-γ upregulates both classes and can induce Class II on cells that normally lack it (e.g., endothelium).

D. Antigen processing and presentation

Peptides are generated by two distinct pathways feeding the two MHC classes.

1. Endogenous (cytosolic) pathway → Class I:
   • Source: Proteins in the cytosol (viral, self, tumour).
   • Degradation: The proteasome cleaves proteins into peptides.
   • Transport: TAP (transporter associated with antigen processing) pumps peptides into the endoplasmic reticulum.
   • Loading: Peptides bind newly assembled Class I with help of the peptide-loading complex (tapasin, calreticulin, ERp57); the complex then travels to the surface.
2. Exogenous (endocytic) pathway → Class II:
   • Source: Extracellular proteins taken up by endocytosis/phagocytosis.
   • Degradation: Acidic endosomes/lysosomes with cathepsins break proteins down.
   • Invariant chain (Ii): Occupies the Class II groove during assembly; degraded to leave CLIP in the cleft.
   • Exchange: HLA-DM removes CLIP, allowing antigenic peptide to bind before surface display.
   • Cross-presentation: Dendritic cells route some exogenous antigen into the Class I pathway to prime CD8⁺ T cells against pathogens that do not infect them directly.

III. B Lymphocytes

The antibody-producing lineage and its receptor

A. B cell receptor and activation

The BCR is membrane-bound immunoglobulin that both recognises antigen and triggers activation.

• Structure: A membrane immunoglobulin (mIgM/mIgD) with antigen-binding Fab arms, associated with the signalling heterodimer Igα/Igβ (CD79a/CD79b).
• Signalling motif: Igα/Igβ carry ITAMs (immunoreceptor tyrosine-based activation motifs) whose phosphorylation launches the cascade.
• Recognition: Binds native, unprocessed epitopes—conformational or linear—unlike the TCR.
• Signal transduction: Antigen cross-links BCRs → Src-family kinases (Lyn) phosphorylate ITAMs → Syk activation → downstream PLCγ2, Ras, NF-κB pathways.
• Co-receptor: CD19/CD21/CD81 complex; CD21 binds complement-tagged antigen, lowering the activation threshold ~1000-fold.

Two routes of activation depending on antigen type:

1. T-dependent: Protein antigens; B cell internalises antigen, presents peptide on Class II to a helper T cell that supplies CD40L–CD40 signal and cytokines—yields class switching, affinity maturation and memory.
2. T-independent: Polymeric antigens (e.g., LPS, polysaccharides) cross-link many BCRs directly—rapid IgM response, little memory or switching.

B. B-cell maturation

B cells develop in the bone marrow through stages defined by immunoglobulin gene rearrangement.

• Site: Antigen-independent phase occurs in the bone marrow.
• Ordered rearrangement (V(D)J):
  • Pro-B: Heavy-chain D–J then V–DJ joining begins; RAG-1/RAG-2 enzymes mediate recombination.
  • Pre-B: Functional μ heavy chain pairs with surrogate light chain to form the pre-BCR, signalling successful rearrangement (allelic exclusion).
  • Immature B: Light-chain rearrangement completes; surface IgM expressed.
  • Mature B: Co-expresses IgM and IgD via alternative splicing; exits to periphery.
• Central tolerance: Immature B cells strongly bound by self-antigen undergo clonal deletion, anergy or receptor editing (renewed light-chain rearrangement to change specificity).

IV. T Lymphocytes

Receptor structure and thymic development

A. T-cell receptors

The TCR is a membrane-bound, non-secreted heterodimer that recognises peptide–MHC.

• Structure: Most T cells carry an αβ heterodimer; a minority carry γδ. Each chain has a variable and constant domain, resembling one Fab arm.
• CD3 complex: TCR associates with invariant CD3 (γ, δ, ε) and ζ chains bearing ITAMs; the TCR itself has no signalling tail.
• Dual recognition: The variable regions contact both the peptide and the surrounding MHC α-helices—the molecular basis of MHC restriction.
• Co-receptors: CD4 binds Class II; CD8 binds Class I—defining helper versus cytotoxic subsets.
• Diversity: Generated by V(D)J recombination of α (V, J) and β (V, D, J) segments plus junctional diversity; the CDR3 loop carries the greatest variability and contacts the peptide.

B. T-cell maturation

T-cell progenitors migrate from bone marrow to the thymus to complete development.

• Site: The thymus; progenitors enter as double-negative (CD4⁻CD8⁻) cells.
• β-selection: A rearranged β chain pairs with pre-Tα to form the pre-TCR, licensing proliferation.
• Double-positive stage: Cells co-express CD4 and CD8 and complete α-chain rearrangement, producing a surface αβ TCR.
• Single-positive stage: Following selection, cells retain either CD4 or CD8 and leave as mature naïve T cells.

C. Thymic selection of T-cells

Selection shapes a repertoire that is both self-MHC-restricted and self-tolerant.

1. Positive selection (thymic cortex):
   • Criterion: TCRs that bind self-MHC with low/moderate affinity receive a survival signal.
   • Presenting cell: Cortical thymic epithelial cells display self-peptide–MHC.
   • Outcome: Ensures MHC restriction; CD4/CD8 lineage commitment follows MHC class recognised. Non-binding cells die by neglect.
2. Negative selection (corticomedullary junction/medulla):
   • Criterion: TCRs binding self-peptide–MHC with high affinity are deleted (clonal deletion) or diverted to regulatory fate.
   • Presenting cells: Medullary epithelium and dendritic cells; the transcription factor AIRE drives expression of tissue-restricted self-antigens here.
   • Outcome: Establishes central tolerance, removing autoreactive clones.
   • Net attrition: Roughly 95–98% of thymocytes die during selection, chiefly by neglect and negative selection.

The two lineages thus converge: MHC molecules manufacture the peptide displays, thymic selection tunes the TCRs that read them, and bone-marrow maturation with peripheral T-cell help arms the antibody response—together producing a specific, self-tolerant adaptive system.