# Defining the role of ligand spatial organization in T cell signaling with DNA origami

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $69,500

## Abstract

Project Summary
 Understanding and manipulating cell signaling processes is crucial for adoptive cell therapies (ACT), which
show significant promise in treating diseases such as cancer and diabetes. Many of the current challenges in
manufacturing these therapeutics are related to our lack of control over ex vivo T cell activation. Though
tremendous progress has been made in understanding how extracellular signaling cues influence intracellular
states, our understanding of detailed mechanisms governing these processes is incomplete. Mounting evidence
suggests that cell signaling is regulated by the physical arrangement of signaling structures at the surface of
cells. However, determining how the spatial arrangement of signaling structures guides cell behavior is very
difficult due to the nanoscale size of these structures, which is below the resolution limit of traditional light
microscopy.
 This study will provide crucial information towards elucidating the role of spatial organization in T cell regulation,
as well as test the feasibility of novel tools I have designed to study and manipulate structures on the nanoscale.
The objective of this study is to determine how 3D spatial arrangements of signaling molecules affect T cell
behavior. To do this, I will arrange ligands into nanoscale 3D patterns, then present these patterned ligands to
T cells and characterize signaling dynamics, as well as T cell manufacturing parameters such as T cell
proliferation rate and IL-2 secretion. The rationale for this work is that by defining the relationship between ligand
arrangement and T cell signaling, we will better understand how the organization of signaling molecules at the
cell surface regulates intracellular pathways, which will guide the development of optimized reagents for efficient
ex vivo T cell activation. I will accomplish this goal using an integrated approach drawing from nanotechnology,
biochemistry, and cell biology. This project will conduct three Specific Aims: 1) determine the relationship
between extracellular receptor kinase dynamics and 3D stimulatory ligand arrangement, 2) determine the spatial
dependence of inhibitory receptors on T cell activation, and 3) create patterned T cell signaling reagents that
can trigger ex vivo primary T cell activation. My project is highly innovative because it will use DNA origami as a
method to pattern ligands with single nanometer-resolution, a degree of precision rivaled only by advanced
cleanroom techniques such as electron beam lithography. This project’s significance lies in defining the
relationship between the spatial organization of signaling molecules and intracellular pathways, and in
establishing the foundation for nanopatterned immunotherapy reagents. This knowledge will allow us to more
deeply understand the mechanisms underlying T cell activation and differentiation, enabling efficient and
efficacious manufacturing of cell therapies for cancer, diabetes, and other diseases.

## Key facts

- **NIH application ID:** 10680089
- **Project number:** 1F32GM147967-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Konlin Shen
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $69,500
- **Award type:** 1
- **Project period:** 2023-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10680089

## Citation

> US National Institutes of Health, RePORTER application 10680089, Defining the role of ligand spatial organization in T cell signaling with DNA origami (1F32GM147967-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10680089. Licensed CC0.

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