Immunology

The Journey to the Node: Why Antigen Has to Travel

Logistics problem

Naive lymphocytes can't realistically patrol every tissue in the body looking for their one matching antigen.
Solution: bring the antigen to a central meeting point instead — a draining lymph node or the spleen.
Dendritic cells are the main couriers — most efficient at retracting their processes and relocating once loaded with antigen.

What flips a dendritic cell from "capture mode" to "delivery mode"

PRR engagement (e.g., TLR)→ Local inflammatory cytokines→ DC upregulates CCR7→ Endothelial chemokines pull DC into lymphatics→ DC settles in node paracortex

Same CCR7 signal is used by naive T cells to home to the paracortex — sender and receiver converge on the same address.
Once activated, a DC's job description flips: it stops trying to capture more antigen and switches to display/presentation mode.
If local damage is extensive enough, antigen (or antigen-bearing cells) can instead wash into the bloodstream and get filtered out in the spleen.

Either route — lymph or blood — ends at the same kind of destination: an organized secondary lymphoid structure built for lymphocyte–antigen encounters.

Lymph Node: A Filter With Zones

Structure

Afferent lymphatic→ Subcapsular sinus→ Cortex (follicles)→ Paracortex→ Medulla/medullary sinus→ Efferent lymphatic

Zone	Dominant cell type	Role
Cortex / follicles	B cells	Site of B-cell activation; germinal centers form here during a response
Paracortex	T cells	Naive T cells arrive via high endothelial venules and meet DC-displayed antigen
Medulla	Plasma cells, macrophages	Antibody-secreting cells concentrate before lymph exits

Fibrous capsule encloses the whole node; afferent vessels pierce it to deliver lymph.
All lymph ultimately drains into the thoracic duct, which returns it to venous blood.

Spleen: The Filter for Blood-Borne Antigen

Structure

Splenic artery enters at the hilum and branches into arterioles.
Each arteriole is sleeved by a cuff of lymphocytes — the periarteriolar lymphoid sheath (PALS), which is T-cell predominant.
Follicles (B-cell rich, with a germinal center once activated) sit adjacent to the PALS — together these make up white pulp.
Arterioles empty into vascular sinusoids — this is red pulp, where old/damaged red cells and blood-borne pathogens get filtered.
Blood exits via splenic vein into the portal circulation.

Rule of thumb: lymph node = tissue-derived antigen; spleen = blood-derived antigen. Same underlying architecture logic, different fluid.

The Three Professional Antigen Presenters

Compare and contrast

APC	Antigen recognition	Co-stimulatory expression	Class II expression	Main downstream effect
Dendritic cell	Non-specific capture (PRRs)	Constitutive — ready immediately	Constitutive, boosted by IFN-γ	Primes naive Th cells — the initiating APC
Macrophage	Phagocytosis of microbes	Inducible (needs IFN-γ/TLR signal)	Low/absent at rest, induced by IFN-γ	Drives the effector phase of a Th1/cell-mediated response
B cell	Specific — via surface B-cell receptor	Inducible (T cell/B7 contact)	Constitutive, boosted by IL-4	Supports a Th2/humoral response

Dendritic cells are the only one of the three that doesn't need activation first to present effectively — that's what makes them the lead initiator.
B cells are unique among APCs in recognizing antigen through an antigen-specific receptor rather than generic uptake.

Loading MHC Class II: Handling What's Outside the Cell

Exogenous pathway

Purpose: display peptides from material the cell engulfed — extracellular bacteria, toxins, debris.
Newly made class II molecules are unstable and "sticky" — they need a placeholder to avoid accidentally binding random cytosolic peptides too early.

Class II made in ER→ Invariant chain (Ii) binds groove→ CLIP fragment blocks the peptide site→ Complex traffics to endocytic/lysosomal compartment→ HLA-DM swaps CLIP for a higher-affinity phagocytosed peptide→ Loaded MHC II → cell surface→ Recognized by CD4+ T cell

If no peptide out-competes CLIP for the groove, the class II molecule is unstable and gets degraded — it never reaches the surface.

Loading MHC Class I: Handling What's Inside the Cell

Endogenous pathway

Purpose: display peptides made or replicating inside the cell — viral proteins, mutated tumor proteins, or pathogen protein that escaped a phagosome into the cytosol.

Cytosolic protein tagged with ubiquitin→ Degraded by proteasome→ Peptide fragments shuttled by TAP complex→ Tapasin bridges TAP to empty class I in the ER→ Peptide loaded onto class I→ Complex → Golgi → cell surface→ Recognized by CD8+ T cell

▶ MHC class I loading pathway · @StepWiseUSMLE

Like class II, an empty class I molecule is unstable — no peptide, no stable surface expression.

Quick contrast: exogenous → class II → CD4+ T cells. Endogenous → class I → CD8+ T cells.

Cross-Presentation: When a Dendritic Cell Borrows Both Pathways

DC-specific trick

Normally, class I only displays what a cell made itself — but dendritic cells can break that rule.
A DC can engulf an entire virus-infected cell and route some of that internalized viral protein into its own class I loading pathway (not just class II).
Net effect: the same DC can simultaneously prime a CD4+ helper T cell (via class II) and a CD8+ cytotoxic T cell (via class I) against the same pathogen.
Physical proximity of these two priming events matters — CD4+ help (e.g., IL-2 production) is often needed to fully convert a naive CD8+ T cell into an effector cytotoxic T lymphocyte and memory cell.

This is how the immune system generates a killer T-cell response against viruses even when the virus doesn't directly infect a dendritic cell.

Clinical Correlate: Targeting the Proteasome in Cancer

Pharmacology

Cancer cells rely heavily on the ubiquitin–proteasome system to keep cycling — including degrading proteins that would otherwise restrain growth (e.g., p53).
Blocking the proteasome lets these regulatory proteins pile up instead of being destroyed.
Net result: cell-cycle arrest and apoptosis in the malignant cell.

Drug	Clinical use
Bortezomib	Multiple myeloma, mantle cell lymphoma
Carfilzomib	Multiple myeloma

Conceptual link back to antigen presentation: the same proteasome machinery these drugs block is what normally feeds peptides into the MHC class I pathway.

Quick-Fire Exam Pearls

Rapid review

CCR7 is the shared "meet-up" signal for activated DCs and naive T cells in the paracortex.
Dendritic cells need no activation step to present antigen — that's their defining edge over macrophages and B cells.
CLIP occupies the MHC class II groove until HLA-DM swaps it for a real peptide.
TAP + tapasin = the endogenous pathway's delivery system into the ER for MHC class I loading.
Exogenous → MHC II → CD4+. Endogenous → MHC I → CD8+. Cross-presentation is the DC exception that lets both happen from one engulfed source.
Empty MHC I or II (no bound peptide) is unstable and degraded before reaching the surface — peptide loading is a stability requirement, not just a display requirement.