Leukocyte Activation

BIOGRAPHY

John Foster is an Associate Faculty Member who works with Steve Ward to evaluate the literature relevant to their research interests.

ACADEMIC POSITION:
BBSRC/Pfizer-funded PhD Student

CURRENT RESEARCH INTERESTS:
Expression and function of P2X7R in human CD4 T lymphocytes

Purine nucleotides, including ATP, are established regulators of inflammatory processes and mediators of immune pathologies. The P2X receptor family is a group of ATP gated cation channels; a member of this family, the P2X7R, has been implicated in several aspects of immune regulation including IL-1 processing and loss of cell surface L-selectin (CD62L) expression in a B lymphoma cell line (B-CLL).

The aims of this project are:

• To confirm the expression of P2X7R on human T lymphocytes at the messenger RNA and protein levels as well as demonstrating ion channel function using whole cell patch clamp electrophysiology. In immune cells ATP has been shown to cause generation of reactive oxygen species and the formation of membrane associated pores. We employ fluorescent dye based assays to measure the effect of ATP on these processes in human T lymphocytes.

• Expression of the chemokine receptor CCR7 and the adhesion molecule L-selectin (CD62L) by naive T lymphocytes is essential for their trafficking to secondary lymphoid organs (SLOs) to survey for antigens. ATP, through the activation of P2X7R, has been implicated in the down-regulation of CD62L in B-CLL, mouse naive CD4 T lymphocytes and human peripheral blood mononuclear cells (PBMCs).

The second aim of this project is to determine the role of P2X7 in the down-regulation of CD62L on primary human naive CD4 T lymphocyte following ATP stimulation. Further to this we wish to elucidate the cellular signalling mechanisms which facilitate CD62L down-regulation following ATP stimulation. The signalling mechanisms involved in the down-regulation of CD62L following activation of the T cell receptor expressed on mouse naive CD8 T lymphocytes have been shown to involve PI3K, Erk1/2 MAPK and mTOR.

The signalling components of these pathways present promising tractable targets for treating autoimmune conditions. However it must first be established if the same signalling mechanisms are responsible for CD62L down-regulation in human T lymphocytes and to see if these pathways are involved in ATP mediated CD62L down-regulation, it is our goal to answer these questions.