Deviation from physiologically appropriate oxygen levels alters proliferation, cytokine production and proximal antigen receptor signalling in CD4+ memory T cells

Background Immune cells must adapt to highly variable oxygen levels encountered across different tissues of the body. Under inflammatory conditions, oxygen levels may reach further extremes, for example healthy synovial joints display oxygen levels of 6-10%, which drop to <5% in rheumatoid arthritis. In contrast, most in vitro experiments are performed under atmospheric oxygen (~21%), raising concerns that experimental conditions do not accurately reflect the physiological microenvironment of the disease being modelled. Aim To explore the role of oxygen levels (21%, 8.5%, 3% and 1% oxygen) on human memory CD4+ T cell function. Results At oxygen levels reflective of physiologically healthy conditions we observed increased proliferative capacity and reduced pro-inflammatory cytokine production of CD4+ memory T cells. Altered patterns were observed in both hyperoxic and hypoxic conditions. A critical component of TCR proximal signaling, Lck phosphorylation, was altered in resting T cells equilibrated to varying oxygen levels. The highest ‘activated’ state was seen at physiologically healthy oxygen levels, suggesting prior oxygen exposure can determine subsequent signaling responses. Conclusion We conclude that environmental oxygen levels significantly influence CD4+ memory T cell responses, with implications for their function in inflammatory sites in vivo. These differences need to be taken into account when designing or interpreting in vitro experiments, as well as harnessing T cells therapeutically.