explain the role of memory cells in the secondary immune response and in long-term immunity

Memory Cells, the Secondary Immune Response and Long‑Term Immunity

Learning Objectives (AO1‑AO3)

• Describe the cellular and molecular events of the primary immune response (AO1).
• Explain how memory B‑cells and memory T‑cells are produced (AO2).
• Analyse why the secondary response is faster, stronger and longer‑lasting than the primary response (AO2).
• Interpret quantitative data (lag time, antibody titre, kinetic curves) for primary and secondary responses (AO3).
• Apply the concepts to vaccination, booster programmes and clinical situations such as immunosenescence (AO2‑AO3).

1. Overview of Immunity (Key‑Concept Links)

2. Primary Immune Response

Key Cellular Players

• Antigen‑presenting cells (APCs): macrophages, dendritic cells and B‑cells process antigen and display peptide fragments on MHC molecules.
• Naïve B‑cells: express membrane‑bound IgM that recognises native antigen.
• Naïve CD4⁺ helper T‑cells: recognise peptide‑MHC II complexes; differentiate into Th1, Th2, etc.
• Naïve CD8⁺ cytotoxic T‑cells: recognise peptide‑MHC I complexes (important for intracellular pathogens).

Sequence of Events (Primary Response)

1. Pathogen is phagocytosed → antigen is degraded → peptide‑MHC complexes appear on the APC surface.
2. Naïve CD4⁺ T‑cells bind peptide‑MHC II → receive co‑stimulatory signal (CD28‑B7) → proliferate & differentiate (Th1, Th2, etc.).
3. Th2 cells secrete IL‑4, IL‑5, IL‑13 → stimulate naïve B‑cells to proliferate.
4. Activated B‑cells undergo:

   • Clonal expansion.
   • Class‑switch recombination (IgM → IgG, IgA or IgE).
   • Somatic hypermutation in germinal centres → modest increase in affinity.

5. Effector B‑cells differentiate into short‑lived plasma cells → secrete low‑affinity IgM (detectable after ~5–7 days).
6. A proportion of activated B‑cells become memory B‑cells; a proportion of activated T‑cells become memory T‑cells.

Quantitative Features (Primary Response)

• Lag time before detectable antibody: ≈5–7 days.
• Peak titre: low‑to‑moderate (≈10⁻⁸ M).
• Dominant antibody class: IgM → low‑affinity IgG.
• Growth kinetics: exponential but with a relatively low slope (k₁).

3. Generation of Memory Cells

• Memory B‑cells retain the high‑affinity, class‑switched B‑cell receptor generated after somatic hypermutation.
• Memory T‑cells retain a T‑cell receptor specific for the same peptide‑MHC complex.
• Both migrate to peripheral lymphoid tissue (spleen, lymph nodes) and circulate in the blood, ready for rapid re‑activation.
• Long‑lived plasma cells, usually resident in bone‑marrow niches, continue low‑level IgG secretion for years.

4. Secondary (Memory) Immune Response

Why It Is Faster, Stronger and Longer‑Lasting

• Higher precursor frequency: memory B‑cells ≈10⁻³–10⁻⁴ of total B‑cells vs. ≈10⁻⁶ for naïve B‑cells.
• Lower activation threshold: fewer co‑stimulatory signals are required.
• Pre‑existing antibodies: low‑level IgG from the primary response can neutralise pathogen immediately.
• Rapid antigen presentation: memory B‑cells act as efficient APCs, presenting antigen to helper T‑cells more quickly.
• Cytokine burst (IL‑2, IL‑4, IFN‑γ) amplifies proliferation of both B‑ and T‑memory cells.

Outcome of the Secondary Response

• Lag time reduced to 1–3 days.
• Peak antibody titre rises dramatically (≈10⁻⁶ M or higher).
• Predominant antibody is high‑affinity IgG (often IgG₁ or IgG₃).
• Affinity maturation continues, producing antibodies up to 100‑fold higher affinity than in the primary response.
• Protection can last months to a lifetime.

Comparison: Primary vs. Secondary Response

5. Antibody Structure & Affinity Maturation (AO1)

• Each antibody = 2 heavy (H) + 2 light (L) chains.

  • Fab region – variable (V) domains bind antigen.
  • Fc region – constant (C) domains mediate complement activation, opsonisation and interaction with Fc receptors.

• Somatic hypermutation introduces point mutations into the V‑region genes of germinal‑centre B‑cells; selection favours clones with higher affinity.
• Class‑switch recombination replaces the constant region (Cμ → Cγ, Cα or Cε) without altering antigen specificity, allowing IgG to cross the placenta and engage Fcγ receptors.

6. Long‑Term Immunity (AO2)

Two cellular reservoirs sustain protection after the primary exposure:

1. Memory lymphocytes – can be re‑activated indefinitely upon re‑encounter with the same antigen.
2. Long‑lived plasma cells – reside in bone‑marrow niches, secreting IgG continuously at a low rate.

The steady‑state serum concentration of antibody is described by:

\$\$

[Ab]{\text{steady}} = \frac{P}{k{\text{deg}}}

\$\$

where P = rate of production by plasma cells and k_deg = degradation constant (IgG half‑life ≈21 days).

7. Cytokines & Chemokines that Amplify the Secondary Response (AO2)

• IL‑2 – promotes proliferation of activated T‑cells.
• IL‑4 & IL‑5 – drive B‑cell differentiation and class‑switch to IgG/IgE.
• IFN‑γ – enhances macrophage microbicidal activity and promotes IgG₁ production.
• CXCL13 – attracts B‑cells to germinal centres, supporting affinity maturation.

8. Clinical Relevance (AO2‑AO3)

• Vaccination – introduces a harmless antigen (live‑attenuated, inactivated, subunit, or mRNA) to generate memory cells without disease.
• Booster doses – re‑expose the immune system, expanding the memory pool and raising antibody titres.
• Immunosenescence – ageing reduces naïve‑cell output and impairs memory‑cell function, lowering vaccine efficacy.
• Immunodeficiency – defects in B‑cell development (e.g., X‑linked agammaglobulinaemia) or T‑cell help (e.g., HIV) impair memory formation.

9. Practical Skills (Paper 3 & Paper 5)

10. Suggested Diagram (AO1)

Flowchart (to be drawn by the student):

1. Primary response – antigen uptake → naïve B/T activation → effector cells + memory cells.
2. Memory phase – long‑lived plasma cells in bone marrow & circulating memory B/T cells.
3. Secondary response – rapid re‑activation of memory cells → high‑affinity IgG production.

Summary (AO2)

Memory B‑cells and memory T‑cells are the cornerstone of the secondary immune response. Their higher numbers, lower activation thresholds, and ability to produce high‑affinity IgG antibodies make the response faster, stronger and longer‑lasting than the primary response. This immunological memory underpins vaccination, booster programmes and the durable protection that characterises successful immunity against many pathogens.