# The mechanochemical control of T-cell directional migration under flow

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $431,815

## Abstract

The mechanochemical control of T-cell directional migration under flow
Daniel A. Hammer (PI) and Janis K. Burkhardt (co-Investigator)
Project Summary
 T-lymphocytes are key players in the adaptive immune response, and motility is critical to their function. T-
cells are equipped with multiple different adhesion molecules that interact with ligands that are expressed
differentially throughout the immune system. Furthermore, T-cells often must act under an imposed flow field
as they traffic through the vasculature and lymphic system. Our goal is to understand how T-cells respond to
the different adhesion ligands and shear rates they encounter to effectively migrate to sites of inflammation and
immune communication. Understanding this process at the molecular level is important for development of
therapeutic strategies to treat inflammatory and infectious diseases, and cancer
 Recently, we have discovered that directional T-cell migration varies as a function of the type of ligand they
encounter and the shear rate to which they are exposed. When placed on a surface bearing vascular cell
adhesion molecule-1 (VCAM-1), which engages the 1-integrin receptor VLA-4, T-cells crawl downstream
under flow (in the direction of flow). However, when placed on a surface bearing intercellular adhesion
molecule-1 (ICAM-1), which engages the 2-receptor LFA-1, T-cells crawl against the direction of flow, like a
salmon swims upstream. The magnitude of upstream migration depends on shear rate, with T-cells more
committed to upstream migration as the shear rate increases. On surfaces in which adhesion molecules are
mixed, any amount of ICAM-1 supports upstream migration. When the flow is removed, T-cells exhibit
migrational memory, but only if they have been exposed to both ICAM-1 and VCAM-1. This observation points
to a novel mechanism of crosstalk between two distinct integrin receptors.
 We propose to investigate the mechanisms that drive the upstream migration of T-cells under flow on
ICAM-1, and the origins of migrational memory. We hypothesize that upstream migration is caused by 2
integrin forming a catch bond, which holds the cell in place while signals generated by integrin ligation
strengthen adhesive interactions and spur the polymerization of actin at the leading edge, driving forward
migration. To test this, we will use molecular engineering, flow chambers, micropatterned surfaces, and
microfabricated post array detectors (mPADs) to measure forces exerted by the migrating cell. We have
preliminary evidence that other motile amoeboid cells such as the immortalized KG1a cell line display the
same phenomenon, facilitating our use of molecular engineering tools and imaging methods to identify the
relevant molecules. By dissecting the mechanisms that underlie this fascinating phenomenon, we expect to
elucidate key features of integrin-dependent T cell trafficking. Our aims in this work are to: 1. Measure the
dynamics of T-cell and KG1a directional motion and ...

## Key facts

- **NIH application ID:** 9988445
- **Project number:** 5R01GM123019-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Daniel A Hammer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $431,815
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988445

## Citation

> US National Institutes of Health, RePORTER application 9988445, The mechanochemical control of T-cell directional migration under flow (5R01GM123019-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9988445. Licensed CC0.

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