Apoptotic-Cell Accumulation and Mertk Expression Are Linked to Diminished Antiviral CD8T Cell Immunity in Chronic Infections
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
Exhaustion of antiviral immunity driven by inhibitory signals is one hallmark of persistent viral infection. Notably, PD-1 and IL-10 are two major contributors to CD8T cell dysfunction. How these molecules are specifically induced during chronic viral infection remains mainly unknown. Using the lymphocytic choriomeningitis virus model, we show that the apoptotic-cell accumulation and expression of tyrosine kinase Mertk are linked to the outcome of chronic viral infection. Early CD8T cell activation correlated with increased dead-cell deposition, rapid induction of IL-10 and TGF-β in macrophages and dendritic cells (DCs), and a pronounced upregulation of PD-1 on CD8T cells and its ligand PD-L1. In TCR-β-deficient mice lacking CD8T cells, dead-cell generation and expression of IL-10, TGF-β, PD-1, and PD-L1 were markedly restricted. Our findings suggest that CD8T cell-mediated killing of infected targets generates large quantities of apoptotic cells, which activate the phosphatidylserine-binding kinase Mertk on macrophages and DCs. This signalling cascade subsequently promotes expression of IL-10, TGF-β, PD-1, and partially PD-L1. Consistent with this model, loss of Mertk inmice reduced inhibitory cytokines and PD-1 expression, accelerated antiviral CD8T cell responses, and improved viral control. Collectively, our study provides important insight into cellular basis of T cell regulation identifying apoptotic cells and Mertk activation as key mechanisms initiating the suppressio
Abstract
Exhaustion of antiviral immunity driven by inhibitory signals is one hallmark of persistent viral infection. Notably, PD-1 and IL-10 are two major contributors to CD8T cell dysfunction. How these molecules are specifically induced during chronic viral infection remains mainly unknown. Using the lymphocytic choriomeningitis virus model, we show that the apoptotic-cell accumulation and expression of tyrosine kinase Mertk are linked to the outcome of chronic viral infection. Early CD8T cell activation correlated with increased dead-cell deposition, rapid induction of IL-10 and TGF-β in macrophages and dendritic cells (DCs), and a pronounced upregulation of PD-1 on CD8T cells and its ligand PD-L1. In TCR-β-deficient mice lacking CD8T cells, dead-cell generation and expression of IL-10, TGF-β, PD-1, and PD-L1 were markedly restricted. Our findings suggest that CD8T cell-mediated killing of infected targets generates large quantities of apoptotic cells, which activate the phosphatidylserine-binding kinase Mertk on macrophages and DCs. This signalling cascade subsequently promotes expression of IL-10, TGF-β, PD-1, and partially PD-L1. Consistent with this model, loss of Mertk inmice reduced inhibitory cytokines and PD-1 expression, accelerated antiviral CD8T cell responses, and improved viral control. Collectively, our study provides important insight into cellular basis of T cell regulation identifying apoptotic cells and Mertk activation as key mechanisms initiating the suppression of CD8T cell immunity during chronic viral infection.