ICa²⁺ Flux, ROS and IL-10 Determines Cytotoxic, and Suppressor T Cell Functions in Chronic Human Viral Infections.

ABSTRACT: 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 iCa²⁺ 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 iCa²⁺ influx, decreased IFN-? and enhanced IL-10 production and this profile is mimicked in Tc1 cells upon reduction of iCa²⁺ flux by extracellular calcium channel inhibitors. Further reduced iCa²⁺ flux induced ROS which lead to IFN-? reduction and increased IL-10 producing T suppressors through the STAT3-STAT5 axis. The above findings were substantiated by our human data where reduced iCa²⁺ flux in chronic Hepatitis infections displayed CD8⁺ T cells with low IFN-? and increased IL-10 production. Importantly treatment with an antioxidant led to increased IFN-? and reduced IL-10 production in human chronic Hep-B/C samples suggesting overall a proximal regulatory role for iCa²⁺ influx, ROS, and IL-10 in determining the effector/ suppressive axis of CD8⁺ T cells.

SUBMITTER: Mohanty S 

PROVIDER: S-EPMC7068714 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature