Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions

Direct measurements revealed low oxygen tensions (0.5-4.5% oxygen) in murin e lymphoid organs in vivo. To test whether adaptation to changes in oxygen tension may have an effect on lymphocyte functions, T cell differentiation and functions at varying oxygen tensions were studied. These studies show: 1) differentiated CTL deliver Fas ligand- and perforin-dependent lethal hit equally well at all redox conditions; 2) CTL development is delayed at 2.5 % oxygen as compared with 20% oxygen. Remarkably, development of CTL at 2.5 % oxygen is more sustained and the CTL much more lytic; and 3) hypoxic expo sure and TCR-mediated activation are additive in enhancing levels of hypoxi a response element-containing gene products in lymphocyte supernatants. In contrast, hypoxia inhibited the accumulation of nonhypoxia response element -containing gene products (e.g., IL-2 and IEFN-gamma) in the same cultures. This suggests that T cell activation in hypoxic conditions in vivo may lea d to different patterns of lymphokine secretion and accumulation of cytokin es (e.g., vascular endothelial growth factor) affecting endothelial cells a nd vascular permeabilization. Thus, although higher numbers of cells surviv e and are activated during 20% oxygen incubation in vitro, the CTL which de velop at 2.5% oxygen are more lytic with higher levels of activation marker s. It is concluded that the ambient 20 % oxygen tension (plus 2-ME) is rema rkably well suited for immunologic specificity and cytotoxicity studies, bu t oxygen dependence should be taken into account during the design and inte rpretation of results of in vitro T cell development assays and gene expres sion studies in vivo.