# Toll-like Receptor Control of MHC Class I Endocytosis

> **NIH NIH R21** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $254,250

## Abstract

PROPOSAL SUMMARY
Cross-presentation is the process whereby major histocompatibility complex class I (MHC-I) molecules are
loaded with peptides derived from an extracellular source of proteins including internalized soluble proteins,
microorganisms and dying cells. Cross-presentation is a specialty of dendritic cells (DCs), cell types responsible
for priming naïve T cells, but even in DCs, this specialty can come naturally or must be acquired upon activation.
Conventional DCs known as cDC1 are potent cross-presenters and can do so constitutively, while inflammatory
monocyte-derived DCs found in inflamed tissues and another subset of conventional DCs, cDC2, can also cross-
present under conditions of infection and inflammation. Parallel to the well-established heterogeneity of DCs in
tissues at steady state and inflammation, DC subsets have different functional states during homeostasis or
inflammation. This functional difference is primarily orchestrated by the engagement of innate signaling receptors,
such as Toll-like receptors (TLRs), that mediate diverse cellular programs including the transcription of
inflammatory genes and mediators, as well as the rapid reorganization of subcellular vesicular traffic through
post-translational events such as phosphorylation. It is imperative that we investigate the full spectrum of DC
functions under inflammation when innate receptors are engaged, and to not be limited to DC classifications as
subsets with rigid inflexible functions. Defining the nature of the inflammatory innate receptors and signals that
enable DCs to augment their cross-presentation capacity or to acquire it anew, will inform vaccine design for
infectious diseases and cancer where cytotoxic CD8 T cells are absolutely essential for organismal survival. A
mechanistic dissection of the regulation of cross-presentation is important for the identification of novel
therapeutic targets that can be exploited to harness CD8 T cell immunity and confer long term protection against
future infection or cancer resurgence. Antigen internalization, processing, and presentation rely heavily on
subcellular vesicular traffic. In vitro tools developed for studying murine conventional DCs have served as the
workhorse responsible for seminal discoveries of the mechanisms of cross-presentation and its regulation, which
have translated to human DC subsets and have impacted vaccine design and cellular therapies. Such tools have
enabled our discovery of endosomal recycling compartment stores of MHC-I critical for cross-presentation and
depleted upon infection by immunoevasive viruses, findings that have been replicated in human DCs. We have
now discovered a new link between cross-presentation of endocytosed antigen and a particular innate receptor
reported to be expressed by cultured DCs, inflammatory DCs and a cDC2 subset. We hypothesize this receptor
intersects MHC-I traffic with endocytic antigen to license cross-presentation during infection. Using cultured a...

## Key facts

- **NIH application ID:** 10453097
- **Project number:** 1R21AI159772-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Julie Magarian Blander
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $254,250
- **Award type:** 1
- **Project period:** 2022-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10453097

## Citation

> US National Institutes of Health, RePORTER application 10453097, Toll-like Receptor Control of MHC Class I Endocytosis (1R21AI159772-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10453097. Licensed CC0.

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