# Synthetic Ligands for Directing Immune Responses

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2022 · $483,676

## Abstract

Abstract:
Dendritic cells (DCs) reside at the interface of innate and adaptive immunity. They can capture
antigens, internalize and degrade them, and present antigen-derived peptides to T cells. The
signals generated in these steps result in the release of cytokines that shape T cell responses.
Due to their roles as critical antigen-presenting cells, DCs are covered with receptors capable of
internalizing antigens—especially lectins. The transmembrane lectins on the DC surface can
bind and internalize glycosylated antigens to influence DC signaling and the cytokines that drive
the differentiation of T cell subsets. As a result, lectins could be exploited to direct vaccines to
dendritic cells and to tailor the immune responses they elicit. The goal of this project is to
develop an understanding of key DC lectins to capitalize on this potential.
 Aim 1 focuses on understanding the combinatorics of lectin engagement and signaling. We
hypothesize that glycans that can bind the toll-like receptors and lectins will bias DC signaling
and therefore T cell responses. We propose to identify candidate glycans with these properties
by assessing the selectivity of DC lectins (DC-SIGN, MGL, dectin-1, dectin-2) for microbial
glycans using glycan arrays. We also will synthesize ligands that can bridge DC lectins and TLRs
to examine the impact of dual engagement directly. In Aim 2, we shall evaluate the hypothesis
that the DC lectins function as mechanosensors. Our preliminary results with DC-SIGN suggest
that particulate antigens and soluble antigens differ in their trafficking. These data suggest that
DC-SIGN can detect differences in stiffness. Pathogens (e.g., viruses, bacteria, fungi) are much
stiffer than human cells, so antigen mechanosensing may be a means of distinguishing foreign
from self. Understanding how antigen stiffness influences lectin and TLR signaling could lead to
new strategies to modulate immunity. In Aim 3, we examine immune responses to antigens that
target DC lectins and TLRs in vivo. The proposed experiments leverage our expertise in
chemical biology to test novel hypotheses regarding the signaling pathways and molecular
mechanisms that underlie how DCs shape T cell responses and, therefore, immunity. Progress
on the proposed Aims is designed to yield new strategies to recruit the immune system to treat
human disease.

## Key facts

- **NIH application ID:** 10397045
- **Project number:** 5R01AI055258-18
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Laura L Kiessling
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $483,676
- **Award type:** 5
- **Project period:** 2003-04-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10397045

## Citation

> US National Institutes of Health, RePORTER application 10397045, Synthetic Ligands for Directing Immune Responses (5R01AI055258-18). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10397045. Licensed CC0.

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