- The interaction of T cells with antigen (Ag) leads to the generation of effector and memory cells. Memory cells have characteristic cell surface marker profiles, and are able to rapidly respond to recall antigens. CD4+ memory cells accumulate in the periphery during aging, following chronic stimulation, and in autoimmune diseases like rheumatoid arthritis (RA). Recently, the applicant has found that the ecto-enzyme gamma glutamyl transpeptidase (GGT) is up-regulated upon T cell activation, and is highly expressed by memory T cells. High levels of GGT are also found in T cells with the capacity to cross endothelial barriers, and on resting peripheral T cells in patients with RA. The role of this enzyme in lymphocyte biology is unclear, but it may be important in maintenance of intracellular re-dox potential and signaling events.
The aims of this application are to 1) determine whether GGT is a better marker of memory T cells than previously described surface Ags; 2) determine the role of GGT in T cell biology; and 3) determine the role of GGT in transendothelial migration of peripheral blood T cells. Experiments proposed include flow cytometric analysis, functional responses of GGT expressing cells to determine if these cells indeed have memory function; and using various strategies to disrupt enzymatic activity, the applicant will test the effect of GGT on activation, growth, and apoptosis. These experiments will provide a thorough description of GGT function in lymphocytes, and should be useful in expanding our knowledge about the memory T cell compartment. GGT also may be a potential target in future immunotherapy strategies.
| Carlisle, Margaret L; King, Miranda R; Karp, David R (2003) Gamma-glutamyl transpeptidase activity alters the T cell response to oxidative stress and Fas-induced apoptosis. Int Immunol 15:17-27 |
| Antczak, C; Karp, D R; London, R E et al. (2001) Reanalysis of the involvement of gamma-glutamyl transpeptidase in the cell activation process. FEBS Lett 508:226-30 |
| Karp, D R; Shimooku, K; Lipsky, P E (2001) Expression of gamma-glutamyl transpeptidase protects ramos B cells from oxidation-induced cell death. J Biol Chem 276:3798-804 |
| Karp, D R; Carlisle, M L; Mobley, A B et al. (1999) Gamma-glutamyl transpeptidase is up-regulated on memory T lymphocytes. Int Immunol 11:1791-800 |
| Henson, S E; Nichols, T C; Holers, V M et al. (1999) The ectoenzyme gamma-glutamyl transpeptidase regulates antiproliferative effects of S-nitrosoglutathione on human T and B lymphocytes. J Immunol 163:1845-52 |
