Antigen-dependent and -independent contributions to primary memory CD8 T cell activation and protection following infection.

Matthew D Martin,Vladimir P Badovinac

doi:10.1038/srep18022

Abstract

Memory CD8 T-cell activation, including expression of IFN-γ and granzymeB, can be induced by antigen (Ag)-dependent signals through the T-cell-receptor, or by pathogen-derived inflammatory cytokines in an Ag-independent manner. Recent studies have come to conflicting results regarding the contributions of Ag and/or inflammation to memory CD8 T-cell activation. Additionally, research has indicated that inflammation-driven CD8 T-cell responses during un-related infections (bystander activation) have the potential to provide protection, but whether protection occurs in immuno-competent hosts is unclear. To investigate these questions, we examined activation of virus-specific memory CD8 T-cells following infection with L. monocytogenes either expressing or not cognate Ag. We show that Ag and inflammation act synergistically in vitro to induce memory activation. In vivo, we found that when memory CD8 T-cells significantly contribute to clearance of infection, early activation and continued responses by these cells are enhanced by cognate Ag recognition. Mechanistically, we show that bystander responses by memory are dependent upon the dose of infection and the amount of inflammation elicited following infection and are able to provide protection in IFN-γ deficient mice, but not in immuno-competent hosts. The data elucidate the requirements for memory CD8 T-cell activation and the protective role of bystander responses.

Highlights

Following infection, memory CD8 T cells become activated and produce effector molecules providing immune hosts with enhanced protection against invading microorganisms[1]
In this study we address the contribution of Ag and inflammation to memory CD8 T cell activation, and protection provided by virus-specific bystander memory CD8 T cells following L. monocytogenes (LM) infection
We have shown that early activation of memory CD8 T cells is enhanced by cognate Ag

Summary

Introduction

Memory CD8 T cells become activated and produce effector molecules providing immune hosts with enhanced protection against invading microorganisms[1]. A different study indicated that the ability of tissue resident memory CD8 T cells to sense infection resulting in the production of IFN-γ , local chemokine production, and the recruitment of immune cells, requires cognate Ag recognition[8] While these conclusions appear to be contradictory, they both could be true if the influence of cognate Ag on memory CD8 T cell activation is context dependent. Multiple studies examining viral infection have indicated that only memory CD8 T cells that recognize Ag due to TCR cross-reactivity are able to provide protection against infection with unrelated viruses[13] It is unclear if bystander responses by memory CD8 T cells provide protection in immuno-competent hosts. Our findings elucidate the role of Ag in memory CD8 T cell activation and protection provided by bystander memory CD8 T cell responses following non-related bacterial infections

Methods

Results

Conclusion