Date of Completion

4-5-2017

Embargo Period

4-4-2019

Keywords

Vγ9Vδ2 T cell, phosphantigen, prodrug, lysis, immunotherapy

Major Advisor

Dr. Andrew Wiemer, Ph.D.

Associate Advisor

Dr. Randall Walikonis, Ph.D.

Associate Advisor

Dr. Akiko Nishiyama, M.D., Ph.D.

Associate Advisor

Dr. Olga Vinogradova, Ph.D.

Associate Advisor

Dr. Steven Szczepanek, Ph.D.

Field of Study

Physiology and Neurobiology

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Vγ9Vδ2 T cells are a subset of T cells which recognize cells containing small charge-negative phosphorous compounds known as phosphoantigens. These phosphoantigens include (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) and isopentenyl diphosphate (IPP) which are produced primarily by microbial organisms (HMBPP) and at low levels in human cells (IPP), but are increased some in cancer cells. The mechanisms involved in Vγ9Vδ2 T cell activation are widely unknown and are continually being uncovered. Here, we investigate the signaling involved in Vγ9Vδ2 T cell activation in both the T cell as well as signaling in the target cell. Using live imaging and flow cytometry in human cells, our studies elucidate the signaling pathways, the pathway of cellular uptake of charge-negative phosphoantigens, and the significance of the phosphoantigen binding protein BTN3A1, in phosphoantigen mediated Vγ9Vδ2 T cell activation. As these phosphoantigens are charge-negative, we also investigate several charge-neutral phosphoantigen prodrugs including POM2-C-HMBP, which readily cross the plasma membrane. These studies show the effects of phosphoantigen prodrugs on Vγ9Vδ2 T cell expansion, target cell lysis by Vγ9Vδ2 T cells, and toxicity in several human cell lines. In vivo analysis has also shown little toxicity of these prodrugs and a humanized mouse model has been established to test expansion of Vγ9Vδ2 T cells and cancer treatment in vivo. Together, these studies expand the knowledge of Vγ9Vδ2 T cell signaling and activation and provide a basis for future studies, particularly the advancement of immunotherapies utilizing Vγ9Vδ2 T cells.

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