iCa(2+) Flux, ROS and IL-10 Determines Cytotoxic, and Suppressor T Cell Functions in Chronic Human Viral Infections

Exhaustion of CD8(+) T cells and increased IL-10 production is well-known in chronic viral infections but mechanisms leading to loss of their cytotoxic capabilities and consequent exhaustion remain unclear. Exhausted CD8(+)T cells also called T suppressors are highly immune suppressive with altered T cell receptor signaling characteristics that mark it exclusively from their cytotoxic counterparts. Our study found that iCa(2+) flux is reduced following T cell receptor activation in T suppressor cells when compared to their effector counterpart. Importantly chronic activation of murine cytotoxic CD8(+) T cells lead to reduced iCa(2+) influx, decreased IFN-γ and enhanced IL-10 production and this profile is mimicked in Tc1 cells upon reduction of iCa(2+) flux by extracellular calcium channel inhibitors. Further reduced iCa(2+) flux induced ROS which lead to IFN-γ reduction and increased IL-10 producing T suppressors through the STAT3—STAT5 axis. The above findings were substantiated by our human data where reduced iCa(2+) flux in chronic Hepatitis infections displayed CD8(+) T cells with low IFN-γ and increased IL-10 production. Importantly treatment with an antioxidant led to increased IFN-γ and reduced IL-10 production in human chronic Hep-B/C samples suggesting overall a proximal regulatory role for iCa(2+) influx, ROS, and IL-10 in determining the effector/ suppressive axis of CD8(+) T cells.