# Mechanoregulation of cytotoxic lymphocyte function

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $572,485

## Abstract

Summary
Immune cells communicate through dynamic cell-cell junctions known as immune synapses. Although the
biochemical properties of these synapses have been studied extensively, we know little about their mechanical
activities and how these activities contribute to immune function. We use cytotoxic lymphocytes as a model
system to investigate the origins and purposes of synaptic force. Cytotoxic lymphocytes fight pathogens and
cancer by forming an immune synapse with an infected or transformed target cell and then secreting toxic
granzymes and the pore forming protein perforin into the intercellular space. Work from our lab and others
suggests critical roles for mechanical forces both in triggering lymphocyte activation and in enhancing the
efficiency of killing responses. Our proposed studies, which are divided into two Specific Aims, will address the
functional relevance and molecular bases of synaptic force in these contexts. Aim 1 builds on preliminary data
indicating that cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells detect the physical stiffening of
target cells and use this mechanosensing capacity to identify and destroy cancer cells invading the metastatic
niche. To determine if and how this mechanical form of immunosurveillance, which we call
mechanosurveillance, shapes anti-tumor immunity in vivo, we will apply multiple murine metastasis models,
atomic force microscopy, and analysis of clinical immunotherapy trials. Aim 2 is premised on prior work
indicating that CTLs use mechanical force to potentiate the pore forming activity of secreted perforin. This sort
of physicochemical synergy demands a high degree of coordination between mechanical and secretory output
within the synapse, but how lymphocytes achieve this coupling remains unknown. We have developed an
imaging-based biophysical approach to address this problem, which will enable us to establish the
mechanochemical choreography of cytotoxicity with unprecedented precision. Our proposed studies will
employ technically innovative methods, including super-resolution imaging of lymphocyte force exertion against
micron-scale biophysical probes. They will also introduce a number of innovative concepts, including the idea
that cellular rigidity can trigger immunosurveillance and the idea that lymphocyte subsets employ distinct
mechanical signatures to specify their effector responses. Our work will also address a simple but technically
vexing issue that has constrained the field for some time, namely whether mechanobiological principles
actually influence immunity in vivo. Understanding the biophysical dimensions of immune synapse function
could potentially reveal new strategies for the modulation and assessment of lymphocyte activity in the clinic.
As such, the studies described herein are highly relevant to the NIH mission in that they will contribute to the
advancement of knowledge that could improve human health.

## Key facts

- **NIH application ID:** 10897112
- **Project number:** 5R01AI087644-14
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Morgan A Huse
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $572,485
- **Award type:** 5
- **Project period:** 2010-02-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897112

## Citation

> US National Institutes of Health, RePORTER application 10897112, Mechanoregulation of cytotoxic lymphocyte function (5R01AI087644-14). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10897112. Licensed CC0.

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