The role of prostaglandin E2 in T cell activation and migration

Abstract

T lymphocytes are important co-ordinators of the immune system during physiology, inlammation and disease. Therefore their regulation by external mediators is of great importance in order to treat immune disorders. One group of T cell-immunomodulators are the lipid mediators prostaglandins. We demonstrate in our studies that the lipid mediator prostaglandin E2 (PGE2) while signaling through EP receptors at physiological nanomolar concentrations is capable of promoting T cell activation, proliferation and differentiation. It was found to enhance Akt signaling in order to aid T cells acheive an efficient activation threshold and hence proceed to the proliferative phase. This EP receptor signaling was also found to be important for Th cell accumulation within draining lymph nodes during inflammation and was vital for the stability of T cell-dendritic cell interactions within the lymph node in vivo. Blocking of these EP recpeptors using specific antagonists on T cells thereby hindered efficient T cell activation, proliferation, Th1, Th17 and T reg differentiation. On the other hand micromolar, inflammatory concentrations of PGE2 were found to be inhibitory to the T cell responses and hence immunosuppressive in nature. EP antagonists blocked in vivo T cell activation and Th1 differentiation in the draining lymph nodes of arthritic mice when administered as a preventive therapy prior to booster dosage of collagen in a mouse model of collagen induced arthritis. %&/In the second part of the thesis we demonstrate that PGE2 at micromolar concentrations inhibits the migration of T cells to the stromal derived factor-1. During T cell activation PGE2 was found to result in the degradation of the cognate receptor CXCR4 following its trafficking to endosomal and lysosomal compartments. T cells when activated and treated with PGE2 aquired a stationary phenotype with the lack of typical migratory structures such as lamellipodia and filopodia. A decrease in total CXCR4 expression in T cells that were activated and treated with PGE2 also lead to a reduction in entry of HIV-1 into T cells.%&/In summary, we conclude that PGE2 has dynamic and concentration-depedent effects on T cell activation and migration and a calculated analysis would help generate future therapeutic tools.