immunology

Immunology · Antigen trafficking & presentation

Core concepts for adaptive immunity · T cell priming · MHC restriction

📌 high-yield This guide integrates migration, lymphoid architecture, and processing pathways.

🔄 Lymphocyte trafficking & secondary lymphoid homing

Professional antigen‑presenting cells (APCs), especially dendritic cells (DCs), capture pathogens in peripheral tissues and migrate to draining lymph nodes. This process is governed by chemokine receptors and inflammatory signals.

  • DC activation: TLR engagement induces pro‑inflammatory cytokines, altering DC phenotype and upregulating CCR7.
  • Chemokine gradient: CCR7 binds CCL19/CCL21 produced by lymphatic endothelium and stromal cells, guiding DCs into afferent lymphatics.
  • Naïve T cell homing: Naïve T cells also express CCR7 and L‑selectin, allowing them to enter lymph nodes via high endothelial venules (HEVs) and encounter antigens in the paracortex.
  • Splenic trapping: Blood‑borne antigens are filtered in the spleen; APCs and antigens enter the marginal zone and are presented to T cells in the periarteriolar lymphoid sheaths (PALS).
💡 Clinical pearl: Defects in CCR7 or its ligands impair DC migration and T‑cell priming, leading to immunodeficiency or increased susceptibility to mucosal infections.

🧬 Architecture of secondary lymphoid organs

Lymph node

  • Cortex: B‑cell follicles (primary & germinal centres).
  • Paracortex: T‑cell zone, rich in DCs and HEVs.
  • Medulla: Medullary cords and sinuses; macrophages and plasma cells.
  • Afferent lymphatics enter via subcapsular sinus; efferent exits at hilum.

Spleen

  • White pulp: PALS (T‑cells) and follicles (B‑cells) surrounding central arterioles.
  • Red pulp: Sinusoids, macrophages; removes old RBCs and blood‑borne pathogens.
  • Marginal zone: Specialised APCs and MZ B cells for blood‑borne antigen capture.
Antigen in tissue→DC uptake + CCR7↑→Afferent lymph→Node paracortex→T‑cell priming

🧪 Exogenous pathway · MHC class II loading

Extracellular pathogens (bacteria, parasites, toxins) are endocytosed, degraded in lysosomes, and loaded onto MHC‑II for presentation to CD4⁺ T cells.

  • Invariant chain (Ii): Associates with newly synthesized MHC‑II in the ER, blocking the peptide groove and directing the complex to endosomal compartments.
  • CLIP fragment: After cleavage of Ii, CLIP remains bound to the groove.
  • HLA‑DM: Catalyses exchange of CLIP for antigen‑derived peptide (higher affinity).
  • Stable peptide‑MHC‑II is transported to the cell surface for recognition by CD4⁺ TCR.
🔬 Key point: Without peptide, MHC‑II is unstable and degraded. HLA‑DM is essential for peptide exchange; defects cause bare lymphocyte syndrome (type II).

🧬 Endogenous pathway · MHC class I loading

Intracellular threats (viruses, tumour antigens) are processed via the ubiquitin‑proteasome system and presented on MHC‑I to CD8⁺ T cells.

  • Ubiquitination targets proteins for proteasomal degradation.
  • Peptides are transported by TAP (transporter associated with antigen processing) into the ER.
  • Tapasin bridges TAP to empty MHC‑I, facilitating peptide loading.
  • Stable peptide‑MHC‑I complexes transit to the surface via Golgi.
⚠️ Clinical correlate: TAP deficiency leads to low MHC‑I expression, impaired CD8⁺ responses, and increased susceptibility to viral infections.

🔄 Cross‑presentation (cross‑priming)

Dendritic cells can internalise infected cells (or apoptotic bodies) and present exogenous antigens on MHC‑I to CD8⁺ T cells — a bridge between innate and cytotoxic immunity.

  • DC phagocytoses virus‑infected cell or tumour fragment.
  • Antigens escape into cytosol or are routed to the ER via TAP‑dependent mechanisms.
  • MHC‑I:peptide complexes are expressed, priming naïve CD8⁺ T cells.
  • This process is augmented by CD4⁺ T‑cell help (IL‑2, CD40L).
🧠 High‑yield: Cross‑presentation is crucial for antitumour immunity and responses against viruses that do not infect DCs directly.

💊 Proteasome inhibitors in oncology

Proteasome inhibition disrupts protein turnover in rapidly dividing tumour cells, leading to accumulation of pro‑apoptotic regulators (e.g., p53, IκB) and cell death.

  • Bortezomib: first‑in‑class; approved for multiple myeloma and mantle cell lymphoma.
  • Carfilzomib: irreversible inhibitor; used in relapsed/refractory myeloma.
  • Side effects: peripheral neuropathy, thrombocytopenia, gastrointestinal symptoms.
Proteasome inhibitor→p53 / cyclins ↑→Cell cycle arrest→Apoptosis

📊 APC subsets and co‑stimulation

APCConstitutive co‑stimMHC‑II expressionPrimary function
Dendritic cellsB7 (CD86), CD40Constitutive, ↑ IFN‑γPrime naïve CD4⁺ Th cells
MacrophagesB7, CD40 (inducible)Low/neg; ↑ by IFN‑γTh1 polarisation, cell‑mediated immunity
B cellsCD40 (constitutive), B7 (inducible)Constitutive, ↑ IL‑4Th2 responses, humoral immunity
📖 Co‑stimulatory molecules — key details
  • B7‑1 (CD80) and B7‑2 (CD86) bind CD28 on T cells; essential for T‑cell activation.
  • CD40 on APCs engages CD40L on activated T cells, enhancing APC function and cytokine production.

⭐ High‑yield USMLE pearls

  • MHC‑I: expressed on all nucleated cells; presents endogenous peptides to CD8⁺ T cells.
  • MHC‑II: restricted to professional APCs; presents exogenous peptides to CD4⁺ T cells.
  • CLIP is removed by HLA‑DM; failure leads to defective antigen presentation.
  • TAP and tapasin are essential for MHC‑I peptide loading.
  • Dendritic cells are the only APCs that can cross‑present and prime CD8⁺ T cells.
  • CCR7 guides both DCs and naïve T cells into lymphoid tissues — disruption impairs immune surveillance.
📝 Recall question (self‑check): Peptides from cytosolic viruses are transported by which complex into the ER for MHC‑I loading?
Answer: TAP complex
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