# Mechanobiology of [alpha][beta]TCRs

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2024 · $779,620

## Abstract

ABSTRACT
Project 1 investigates αβTCR function spanning in vitro single molecule and single cell assays that interrogate
force-dependent mechanosensor activation by peptide/MHC (pMHC) ligands with optical tweezers to in vivo
assays with corresponding retrogenic αβ T cells addressing biological consequences such as naïve T cell
expansion and memory T cell formation and maintenance. Thus, Project 1 couples αβTCR molecular
mechanism with functional biology. From a systems perspective, Project 1 links with Project 2 of the preTCR
(pTαβ) by executing parallel tests on the mature αβTCR. Parameters will also be measured for single cell
activation including the activation threshold, force range for activation and intracellular calcium profile. Project 1
is tightly integrated with NMR and Project 3, where structural and conformational changes as a consequence
of mutations (strengthening, weakening, substitutions) will be defined and mapped onto changes in measured
parameters. At the single molecule level, conformational change(s), force bond lifetime, extension magnitude,
critical force and transition energy landscape will be measured. At the single cell level, the physical and
chemical requirements to trigger (critical force window and pMHC density) will be characterized. TCRs will also
be evaluated in vivo (naïve mouse) for their ability to induce T cell proliferation upon exposure to infectious
pathogens such as influenza A and their ability to form central or tissue resident memory T cells. Single cells
will be triggered at critical force thresholds and then recovered through micropipette aspiration for
transcriptome analysis. The overarching goal is to pair single molecule and single cell measurements of Aim 1
with functional biological impact of Aim 2. Strategically, the project will execute a cycle of measurements
involving single molecule single cell, functional biology, structure biology utilizing NMR and molecular
dynamics to permit refinement of our models and confirmation or rejection of our atomistic hypotheses to
explain αβTCR mechanobiology.

## Key facts

- **NIH application ID:** 10877945
- **Project number:** 5P01AI143565-05
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Matthew J. Lang
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $779,620
- **Award type:** 5
- **Project period:** 2020-07-29 → 2025-09-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877945

## Citation

> US National Institutes of Health, RePORTER application 10877945, Mechanobiology of [alpha][beta]TCRs (5P01AI143565-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10877945. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*