Systemic ATP Levels Suppress the Function of CD4+ T Cells in Sepsis by Impairing Autocrine Purinergic Signaling

Abstract

T cell suppression in critical care patients can cause sepsis. The underlying mechanisms leading to T cell suppression are largely unknown. We have previously demonstrated that T cell activation requires ATP release and autocrine purinergic signaling via P2X receptors. Here we show that systemic ATP released in response to injury and inflammation interferes with these autocrine signaling processes resulting in suppression of CD4+ T cell activation. Using Fluo-4 and flow cytometry, we found that cytosolic Ca2+ signaling in response to T cell receptor (TCR)/CD28 stimulation of CD4+ T cells from sepsis patients was significantly lower compared to healthy controls (Fig. 1A). Plasma ATP levels were ~3 times higher in sepsis patients (101 ± 9 nM) than in healthy controls (31 ± 7 nM; p<0.001). Adding ATP or the non-hydrolyzable ATP analog ATPγS time- and dose-dependently impaired TCR stimulation induced Ca2+ signaling of healthy CD4+ T cells (Fig. 1B; *p<0.05 vs. untreated) and suppressed proliferation of mouse splenocytes by up to 80%. Taken together these findings suggest that elevated systemic ATP in the plasma of critical care patients suppresses the function of T cells by interfering with their autocrine purinergic signaling. Targeting this inhibitory process may improve T cell function and outcome after sepsis. The study was supported by NIH grants R01 GM51477, R01 GM60475, R01 AI080582, T32 GM103702, and DFG grant LE-3209/1-1.