# Mechanisms of antigen cross-presentation by MHC class I molecules

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $418,750

## Abstract

Project Summary
 Virus infected cells express MHC-I molecules associated with virus-derived peptides that
are recognized by cytotoxic CD8+ T cells. The peptides are generated by proteasomal
degradation of viral proteins synthesized in the cytosol and bind to assembling MHC-I heavy
chain-β2microglobulin dimers in the ER. Naïve CD8+ T-cells, however, must be primed to induce
a mature cytotoxic phenotype. Priming is generally mediated by DCs that acquire antigens by
endocytosis and/or phagocytosis to generate the MHC-I-bound peptides, a process called
cross-presentation. The mechanisms of cross-presentation remain poorly understood, with only
a few effectors identified and none are absolutely required. We propose that the reason is that
there is not a single cross-presentation pathway. Literature data points to three pathways. In the
first, phagolysosomal proteases (cathepsins) degrade antigens to generate the peptides in situ
and these bind to recycling MHC-I by peptide exchange. We discount this as a major
mechanism because it would result in a mismatch between the MHC-I-peptide complexes
generated by cross-presentation and those generated by proteasomes in the ultimate cytotoxic
CD8+ T cell target, the virus infected cell. In the second, phagocytosed or endocytosed antigens
are transferred across phagosomal/endosomal membranes into the cytosol where, like the
newly synthesized proteins in virus infected cells, they are degraded by cytosolic proteasomes
to generate peptides. These are translocated into the ER (or phagosomes that have recruited
ER components) by the Transporter associated with Antigenic Processing (TAP) and bind to
assembling MHC-I molecules, which are then transported to the cell surface. We propose to
determine the mechanism(s) of translocation from endocytic compartments to the cytosol. In the
third pathway, rather than internalized antigens entering the cytosol, cytosolic proteasomes are
delivered into the lumen of phagosomes and/or endosomes. The antigens are then processed in
situ by the proteasomes to generate peptides that bind to recycling MHC-I. This pathway is
independent of TAP transport of the antigenic peptides but is dependent on proteasome activity.
We propose that the second and third routes of cross-presentation can both operate, the
common denominator being the endpoint, namely antigen recognition by the CD8+ T cells. The
precise mechanisms required to mount and maintain a successful CD8+ T cell response will be
determined.

## Key facts

- **NIH application ID:** 10276760
- **Project number:** 1R01AI162820-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** PETER CRESSWELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $418,750
- **Award type:** 1
- **Project period:** 2021-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10276760

## Citation

> US National Institutes of Health, RePORTER application 10276760, Mechanisms of antigen cross-presentation by MHC class I molecules (1R01AI162820-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10276760. Licensed CC0.

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