# Probing mesoscale receptor organization in T cell signaling with DNA origami

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $201,875

## 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 to study and manipulate structures on the nanoscale.
Our objective is to determine how 3D spatial arrangements of signaling molecules affect T cell behavior. To do
so, we will use DNA origami nanostructures to arrange ligands into nanoscale 3D patterns, then present these
patterned ligands to T cells and characterize signaling dynamics, we will also assess ACT-relevant parameters
such as T cell proliferation rate and IL-2 secretion. Our rationale 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. This project will leverage nanotechnology, biochemistry, and cell to
accomplish 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.
We will define 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:** 10726455
- **Project number:** 1R21AI178200-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Shawn M Douglas
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $201,875
- **Award type:** 1
- **Project period:** 2023-05-19 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10726455

## Citation

> US National Institutes of Health, RePORTER application 10726455, Probing mesoscale receptor organization in T cell signaling with DNA origami (1R21AI178200-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10726455. Licensed CC0.

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