Date

2013

Document Type

Thesis

Degree

Master of Science

Department

Mechanical Engineering and Mechanics

First Adviser

Zhang, Xiaohui

Abstract

Integrins are a family of transmembrane adhesion proteins that mediatecell attachment to extracellular matrix or to another cell. The Tcell LFA-1 integrin and its interaction with its predominant ligand,ICAM-1, is known to regulate antigen-driven differentiation of naiveT cells into effector T cells, a process that is fundamental to adaptiveimmunity. The activation of LFA-1 on effector and naive T cells isstill unclear and requires further investigation for a more detailedunderstanding. In this work we quantitatively study primary T cells(both naive and effector) and their interaction with ICAM-1 usingatomic force microscopy (AFM). Measurements show that adhesion ofthe effector T cell is in general at least one order of magnitudehigher than that of the naive T cells. OKT3 treatment has a profoundimpact on T cell–ICAM-1 interaction, resulting in at least a 2-foldincrease in both detachment force and work. Our conclusions corroboratepast research that shows that there is a higher expression of LFA-1on effector T cells than naive T cells and that LFA-1 on effectorT cells is predominantly in the high affinity state. Our results alsopossibly indicate that a mixed population of high and low affinityLFA-1 is present on naive cells. Furthermore, given the response toOKT3 treatment, it is likely that it induces populations of LFA-1to change from low affinity to high affinity on both effector andnaive T cells. Taken together, our studies reveal in more detail theregulation and conformational states of high affinity LFA-1 on T cellswhich is critical to T cell activation. Additionally, we use AFM to look at the interaction between neuropilin-2 (NRP-2), a type I transmembrane glycoprotein, which is expressed on cancer cells and show that it interacts with α5 integrin on endothelial cells. Most importantly, our studies reveal that theinteraction mediates cancer cell vascular extravasation and promotesmetastasis. This research further supports the highly promising routeof preventing cancer metastasis by therapeutically blocking NRP-2and thereby greatly improving the prognoses of cancer patients.

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