Adaptive Immunity: B and T Cells

Spec mapping: AQA 7402 Section 3.2.4 — specific (adaptive) immune response (refer to the official AQA specification document for exact wording).

Adaptive immunity is the vertebrate innovation that complements the broad, fast, non-specific innate response (lesson 7) with exquisite antigen specificity and long-lived memory. Each individual maintains a repertoire of approximately 10⁸–10¹¹ different B-cell receptors and T-cell receptors, generated by somatic recombination of receptor genes during lymphocyte development — a diversity vast enough to recognise virtually any antigen the immune system will ever encounter. When a naive B or T cell encounters its cognate antigen, clonal selection activates that specific cell, clonal expansion produces millions of identical daughter cells, and differentiation produces both immediate effector cells (plasma cells, cytotoxic T cells) and durable memory cells that respond faster and stronger on re-encounter. This lesson covers the cellular and molecular architecture of adaptive immunity, the primary vs secondary response, antibody structure and function, and one major application (ELISA). Lesson 9 then covers vaccination, monoclonal antibodies and the ethics of immune-based medicine.

Key Definition: Adaptive (specific) immunity is the antigen-specific, memory-generating arm of vertebrate immunity, mediated by B lymphocytes (producing antibodies — humoral immunity) and T lymphocytes (cell-mediated immunity). Each B or T cell expresses a unique antigen receptor; the rare cell matching a given antigen is selected and expanded by clonal selection.

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Lymphocyte Origin and Differentiation

Both B and T lymphocytes arise from haematopoietic stem cells in the bone marrow. They diverge during maturation:

• B lymphocytes mature in the bone marrow (B is for bone marrow in mammals — historically named for the bursa of Fabricius in birds). Each B cell expresses a unique B-cell receptor (BCR) — a membrane-bound immunoglobulin. Maturation includes negative selection against self-reactive clones (central tolerance).
• T lymphocytes migrate to the thymus for maturation (T is for thymus). Each T cell expresses a unique T-cell receptor (TCR). Thymic education involves both positive selection (T cells with TCRs that bind self-MHC with low affinity survive) and negative selection (T cells that bind self-peptide–MHC complexes too strongly are deleted, preventing autoimmunity).

Mature naive lymphocytes circulate through blood, lymph and secondary lymphoid organs (lymph nodes, spleen, mucosa-associated lymphoid tissue) until they encounter their cognate antigen.

A-Level-depth note (paraphrased): the diversity of receptors is generated by a process called V(D)J recombination — somatic rearrangement of receptor gene segments — which produces an essentially unique receptor in each lymphocyte. This is a key example of where developmental DNA changes generate functional protein diversity. Detail of V(D)J recombination machinery is beyond AQA; the principle that the genome is rearranged in lymphocytes is the key idea.

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T-Cell Subsets

T lymphocytes are subdivided by their TCR and co-receptor expression, which dictates which MHC class they recognise.

Helper T Cells (T_H, CD4⁺)

• Recognise antigen presented on MHC class II by antigen-presenting cells (macrophages, dendritic cells, B cells).
• Once activated, helper T cells secrete cytokines (interleukins, interferons) that orchestrate the immune response:
  • IL-2: stimulates proliferation of T cells (autocrine and paracrine).
  • IL-4, IL-5, IL-13: stimulate B-cell activation and antibody class switching to IgE.
  • IFN-γ: activates macrophages for enhanced phagocytosis.
• Helper T cells are the conductors of the orchestra — their loss (e.g., in advanced HIV infection) causes catastrophic immune failure.

Cytotoxic T Cells (T_C, CD8⁺)

• Recognise antigen presented on MHC class I on virtually any nucleated cell.
• A cytotoxic T cell that recognises a virus-infected cell (displaying viral peptides on MHC I) or a tumour cell (displaying mutated self-peptides) kills the target by:
  • Releasing perforin — a pore-forming protein that punctures the target membrane.
  • Injecting granzymes — serine proteases that activate the target's apoptosis pathway.
  • Engaging Fas ligand on the T cell with Fas on the target, triggering apoptosis.
• The result is targeted destruction of the infected cell, eliminating the viral replication factory.

Regulatory T Cells (T_reg)

• Suppress immune responses to prevent collateral damage and maintain self-tolerance.
• Defects in T_reg function are associated with autoimmune disease.
• The CD4⁺ subset expressing the transcription factor FOXP3 is the canonical T_reg lineage.

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B-Cell Activation and Differentiation

B-cell activation classically requires two signals.

1. Signal 1: BCR binds a cognate antigen on the pathogen surface (e.g., a surface protein on a bacterium). The BCR–antigen complex is internalised by receptor-mediated endocytosis, the antigen is digested, and peptide fragments are loaded onto MHC II on the B-cell surface.
2. Signal 2: An activated helper T cell, with a TCR matching the same antigen's peptide on the B cell's MHC II, binds and provides co-stimulation (CD40L–CD40, plus cytokines IL-4, IL-21).

Following activation, the B cell proliferates (clonal expansion) and differentiates into two cell fates:

• Plasma cells — short-lived (days–weeks) antibody factories that secrete several thousand antibody molecules per second. Hypertrophied RER and Golgi (as discussed in lesson 1) reflect this output. Plasma cells produce the primary-response antibody.
• Memory B cells — long-lived (years–decades) cells that retain the BCR specificity and respond rapidly to re-exposure.

Some activated B cells enter germinal centres in lymph nodes and undergo affinity maturation: the BCR genes undergo somatic hypermutation, generating variants. Variants whose BCR binds antigen most strongly are selected for further proliferation. The result is that the secondary response produces antibody of progressively higher affinity than the primary response — an A-Level-depth subtlety that distinguishes A from A*.

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Antibody Structure

Antibodies (immunoglobulins, Ig) are Y-shaped glycoproteins, each composed of four polypeptide chains held together by disulphide bonds.

Architecture

• Two heavy chains (~50 kDa each) and two light chains (~25 kDa each).
• Each chain has variable (V) regions at the N-terminus and constant (C) regions at the C-terminus.
• The antigen-binding sites are formed at the tips of the Y by the variable regions of one heavy and one light chain. The two binding sites are identical, allowing the antibody to crosslink antigens.
• The Fc region (constant region at the base of the Y) determines effector functions — which immune cells the antibody recruits and which complement pathway it activates.
• Disulphide bonds (–S–S–) covalently link heavy chains to each other and to light chains, stabilising the Y shape.

Isotypes

The five antibody isotypes differ in heavy-chain constant regions and effector functions.

Isotype	Role
IgM	First antibody produced in primary response; pentamer; potent complement activator
IgG	Most abundant in serum; secondary response; crosses placenta giving passive immunity to foetus
IgA	Secreted into mucus, breast milk, saliva; mucosal protection
IgE	Allergic responses; activates mast cells; defence against parasites
IgD	Mainly a B-cell surface receptor; functions less well understood

Antibody Functions

• Neutralisation: antibody binding blocks the active site of a toxin or the receptor-binding domain of a virus.
• Opsonisation: antibody-coated pathogens are recognised by Fc receptors on phagocytes, dramatically enhancing phagocytosis (linking adaptive output to innate phagocytic action).
• Complement activation: IgM and IgG bound to antigen activate the classical complement pathway → MAC, opsonisation, inflammation.
• Agglutination: bivalent antibodies crosslink antigens (e.g., pathogen surfaces) → clumps that are easier to phagocytose.
• Antibody-dependent cell-mediated cytotoxicity (ADCC): NK cells bind antibody-coated targets via Fc receptors and kill them.

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Antibody Structure

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Clonal Selection and Clonal Expansion

The cornerstone of adaptive immunity is clonal selection — first proposed by Macfarlane Burnet in the 1950s, now experimentally established. The theory states that each lymphocyte expresses a single antigen specificity, and antigen selects for proliferation only the rare lymphocyte(s) with matching receptors. Each subsequent daughter cell is a clone with the same specificity.

The contrast with the earlier instructive theory is conceptually important: under the instructive model (now refuted), antigen would template a complementary antibody on naive lymphocytes — a Lamarckian inheritance of acquired form. Clonal selection is Darwinian: variation pre-exists; antigen selects from it. A common A-Level-depth misconception treats antigen as the creator of antibody specificity; this is wrong — antigen selects pre-existing specificities from the lymphocyte repertoire.

Clonal expansion then dramatically multiplies the selected clone. A single activated B cell can give rise to ~10⁵ daughter cells within a week of stimulation, of which plasma cells produce antibody at rates of thousands of molecules per second.

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Primary vs Secondary Immune Response

The primary response to a first encounter with an antigen is slow (5–10 days to detectable antibody), modest in peak antibody titre, dominated by IgM, and short-lived. During the primary response, memory B and T cells are generated.

The secondary response to a re-encounter with the same antigen is fast (1–3 days to peak), much higher in peak antibody titre (often 10–100×), dominated by IgG (class-switched, high-affinity), and long-lived. Memory cells, already abundant and primed, are selected, expanded and differentiated rapidly.

This kinetic difference is the basis of vaccination (lesson 9): a vaccine engineers a controlled primary response so that the recipient's later encounter with the natural pathogen is in effect a secondary response.

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Mermaid Diagram — Primary vs Secondary Antibody Response

flowchart LR
  E1[First exposure] --> P[Primary response slow, low titre, IgM]
  P --> M[Memory cells generated]
  E2[Second exposure same antigen] --> S[Secondary response fast, high titre, IgG]
  M --> S

Plot conceptually: time on x-axis, antibody titre (log scale) on y-axis. The primary response curve peaks around day 10–14; the secondary response curve, triggered on re-exposure many months later, peaks within 3–5 days at a far higher titre. Memory persists for years to decades — for some childhood vaccines, lifelong.

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ELISA — Enzyme-Linked Immunosorbent Assay

ELISA exploits the specificity of antigen–antibody binding to detect and quantify a target molecule (antigen or antibody) in a sample. The assay is widely used in diagnostics (HIV testing, COVID-19 antibody surveillance), pregnancy testing (β-hCG detection), and research.

Direct ELISA

1. Coat the wells of a microtitre plate with antigen from the patient sample.
2. Wash to remove unbound material.
3. Add enzyme-conjugated antibody specific to the target antigen.
4. Wash to remove unbound antibody.
5. Add the enzyme's substrate, which produces a coloured (or fluorescent) product when cleaved.
6. Measure absorbance with a plate reader. Colour intensity is proportional to antigen quantity.

Indirect ELISA

Used to detect patient antibodies (e.g., anti-HIV antibodies indicating prior or current HIV infection):

1. Coat wells with the target antigen (e.g., HIV gp120 protein).
2. Add patient serum. Any antibodies in the serum that bind the antigen are retained.
3. Wash; add a secondary enzyme-conjugated antibody that binds human IgG.
4. Wash; add substrate; measure colour.

Sandwich ELISA

Most sensitive for quantifying antigen at low concentrations:

1. Coat wells with a capture antibody specific for one epitope of the target antigen.
2. Add the sample. Antigen, if present, binds the capture antibody.
3. Add a detection antibody specific for a different epitope on the same antigen — the antigen is "sandwiched".
4. Add an enzyme-conjugated secondary antibody (or use a directly enzyme-conjugated detection antibody).
5. Substrate, colour, plate reader.