Cross-Presentation Pathway: Cytosolic vs Vacuolar Antigen Routing

Antigen Delivery

Antigen dose 12 particles

Pathway Kinetics

Sec61 export rate k₁ 0.60 /s

Cathepsin S rate k₂ 0.60 /s

TAP transporter activity 1.00×

Live Readouts

Surface pMHC-I total

Cross-pres. rate

0.0 /s

Cytosolic 0%Vacuolar 0%

Predicted P(cytosolic)

50.0%

Intact antigen (phagosome) Cytosolic route → peptide → ER → surface Vacuolar route → peptide → surface

How it works

Dendritic cells present pieces of engulfed extracellular antigen on MHC class I, priming CD8⁺ killer T cells — a trick called cross-presentation. Inside the phagosome, each antigen molecule faces two competing exit routes, modelled here as independent Poisson processes:

Cytosolic route:  Sec61 translocon exports antigen (rate k1)
                  → proteasome cleaves it into peptides
                  → TAP1/TAP2 pumps peptides into the ER
                  → loaded onto MHC-I (tapasin/calreticulin)
Vacuolar route:   Cathepsin S degrades antigen in situ (rate k2)
                  → peptides load directly onto phagosomal MHC-I
                  → TAP- and proteasome-independent

Because both are memoryless exponential processes, the time to the first event is Exp(k1+k2), and the identity of whichever fires first follows the classic competing-risks result:

P(cytosolic route) = k1 / (k1 + k2)
P(vacuolar route)  = k2 / (k1 + k2)

k1 (Sec61 export) — how fast antigen escapes the phagosome into the cytosol for proteasomal processing.
k2 (cathepsin S) — how fast antigen is degraded directly inside the phagosome/endosome.
TAP activity — scales how quickly cytosolic peptides reach the ER loading complex; low TAP activity is a well-documented bottleneck that throttles the cytosolic route even when k1 is high.

Watch the measured cytosolic/vacuolar split converge on the predicted k1/(k1+k2) line as more antigen is released — a direct demonstration of competing-risk kinetics in real cell biology.

Dendritic cell body Phagosome ER / TAP loading complex

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