🛡️ T‑lymphocyte activation
Overview: Naive T cells are activated in secondary lymphoid organs after antigen presentation. Two signals are required: TCR–MHC recognition (signal 1) and costimulation (signal 2). Successful activation drives clonal expansion and differentiation into effector and memory cells.
Signal 1: antigen recognition
- TCR binds to peptide–MHC complex on APC.
- CD4 binds MHC class II; CD8 binds MHC class I.
- CD3 complex transduces the signal.
Signal 2: costimulation
- B7‑1 (CD80) / B7‑2 (CD86) on APC bind CD28 on T cell.
- B7 expression increases during infection/inflammation.
- Without signal 2 → T‑cell anergy or tolerance.
⚖️ CTLA‑4 & immune checkpoint
CTLA‑4 (CD152): expressed on activated T cells and Tregs. It competes with CD28 for B7 binding, delivering inhibitory signals. Critical for limiting T‑cell responses and preventing autoimmunity.
Abatacept – RA
Belatacept – renal transplant
Ipilimumab – melanoma, colorectal, other cancers (enhances anti‑tumor immunity)
High‑yield: CTLA‑4 knockout mice develop fatal lymphoproliferation and autoimmunity.
⚠️ Superantigens
Superantigens (e.g., TSST‑1, staphylococcal enterotoxins) cross‑link TCR Vβ domain with MHC class II outside the peptide groove. This activates many T‑cell clones polyclonally, causing massive IFN‑γ release and macrophage activation → cytokine storm (IL‑1, IL‑6, TNF‑α).
🧬 Th1, Th2, Th17 differentiation
Naive Th0 cells differentiate into distinct subsets based on pathogen and cytokine milieu.
| Subset | Inducers | Key cytokines | Effector functions |
|---|---|---|---|
| Th1 | Intracellular pathogens, IL‑12, IFN‑γ | IFN‑γ | Macrophage activation, IgG switching, inhibits Th2 |
| Th2 | Helminths, allergens; IL‑4 | IL‑4, IL‑5, IL‑10, IL‑13 | IgE/IgA switching, eosinophil activation, alternative macrophage |
| Th17 | Extracellular bacteria/fungi; TGF‑β + IL‑6 | IL‑17, IL‑22 | Neutrophil recruitment, antimicrobial peptides, barrier function |
🧘 Treg cells
- Phenotype: CD4⁺, CD25⁺, FoxP3⁺
- Secrete IL‑10 and TGF‑β → suppress Th1/Th2 responses.
- Essential for preventing autoimmunity.
💥 Cytotoxic T lymphocytes (CTL)
CD8⁺ T cells recognize antigen on MHC class I. They require both signal 1 (TCR–MHC I) and costimulation, plus cytokines from Th cells (especially IL‑2) for proliferation and full cytotoxic function.
🧫 B‑lymphocyte activation
Thymus‑independent (TI) antigens
- Lipids, polysaccharides, LPS.
- Directly activate B cells (no T‑cell help).
- Mainly IgM, no memory, weak response.
- Marginal zone B cells and B‑1 cells.
Thymus‑dependent (TD) antigens
- Protein antigens; require CD4⁺ T‑cell help.
- B cell internalizes antigen → MHC II presentation.
- B7 upregulation on B cell.
- CD40L on T cell binds CD40 on B cell → signal 2.
- Leads to germinal center formation, affinity maturation, isotype switching, and memory.
📈 Affinity maturation & isotype switching
Affinity maturation
- Somatic hypermutation in germinal centers → point mutations in V regions.
- B cells with higher affinity outcompete for antigen → clonal selection.
- Average antibody affinity increases over time.
Isotype switching
- Heavy‑chain constant region DNA recombination (switch regions).
- Driven by cytokines from helper T cells.
- One‑way process: once switched, cannot return to IgM.
- IgM predominates in primary response; IgG/IgA/IgE in secondary.
| Cytokine | Isotype induced |
|---|---|
| IFN‑γ | IgG (opsonization, complement) |
| IL‑4 / IL‑13 | IgE (mast cell, basophil, eosinophil) |
| TGF‑β / IL‑5 | IgA (mucosal immunity) |