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-γ 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-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 iCa2+ 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 iCa2+ influx, ROS, and IL-10 in determining the effector/ suppressive axis of CD8+ T cells.
Highlights
Cytotoxic T cell type1 (Tc1), a CD8+ T cell subset, plays crucial roles in clearing viral infections through the active secretion of cytolytic molecules and pro-inflammatory cytokines; IFN-γ, TNF-α Perforin and Gr B [1,2,3,4]
Chronic intra cellular infections are caused by unproductive immune responses to viruses and this continuous inefficient activation leads to T cell exhaustion [10, 20, 45, 46] whereby they lose their ability to secrete pro-inflammatory cytokines and cytolytic proteins [47, 48]
Tc1 cells known to be important for clearance of viral infections through secretion of IFN-γ and cytolytic molecules Gr B and Perforin-c [2, 49, 50] have been shown to change phenotype and secrete IL-10 and this compromised cytotoxic status has been shown to precipitate chronic viral infection(s)
Summary
Cytotoxic T cell type (Tc1), a CD8+ T cell subset, plays crucial roles in clearing viral infections through the active secretion of cytolytic molecules and pro-inflammatory cytokines; IFN-γ, TNF-α Perforin and Gr B [1,2,3,4]. Persistent antigenic presence as evidenced in chronic viral infections such as hepatitis B/C, HIV leads to T cell exhaustion characterized by sustained high expression [5,6,7,8,9,10] of surface inhibitory markers PD-1, Lag-3, CTLA4, and subsequent loss of cytotoxic capabilities [8,9,10,11,12,13,14]. Partial restoration of cytotoxic function in exhausted CD8+ T cells has been reported by blockade of co-inhibitory receptors PD-1, Lag-3 as well as IL-10 receptors in Lymphocytic choriomeningitis and Toxoplasma gondii [5, 23] the exact signaling pathway leading to conversion of effector CD8+ T cells into a T suppressor phenotype is yet undefined. Elucidating the pathway of exhaustion will pave the way for targeting regulatory molecules that may help in complete restoration of function in suppressor T cells
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