NOD1 Cooperates with TLR2 to Enhance T Cell Receptor-Mediated Activation in CD8 T Cells

Blandine C. Mercier,Marie-Laure Fogeron,Martine Tomkowiak,Erwan Ventre,Anne-Laure Debaud,Nathalie Bonnefoy,Jacqueline Marvel,Jörg Hermann Fritz

doi:10.1371/journal.pone.0042170

Blandine C. Mercier, Marie-Laure Fogeron + Show 6 more

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https://doi.org/10.1371/journal.pone.0042170

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Abstract

Pattern recognition receptors (PRR), like Toll-like receptors (TLR) and NOD-like receptors (NLR), are involved in the detection of microbial infections and tissue damage by cells of the innate immune system. Recently, we and others have demonstrated that TLR2 can additionally function as a costimulatory receptor on CD8 T cells. Here, we establish that the intracytosolic receptor NOD1 is expressed and functional in CD8 T cells. We show that C12-iEDAP, a synthetic ligand for NOD1, has a direct impact on both murine and human CD8 T cells, increasing proliferation and effector functions of cells activated via their T cell receptor (TCR). This effect is dependent on the adaptor molecule RIP2 and is associated with an increased activation of the NF-κB, JNK and p38 signaling pathways. Furthermore, we demonstrate that NOD1 stimulation can cooperate with TLR2 engagement on CD8 T cells to enhance TCR-mediated activation. Altogether our results indicate that NOD1 might function as an alternative costimulatory receptor in CD8 T cells. Our study provides new insights into the function of NLR in T cells and extends to NOD1 the recent concept that PRR stimulation can directly control T cell functions.

Highlights

Pattern recognition receptors (PRR) are involved in the detection of microbial infections as well as tissue damage in mammals
We demonstrate that NOD1 stimulation within CD8 T cells enhances their T cell receptor (TCR)-mediated activation, proliferation and effector functions
This effect on CD8 T cells is dependent on TCR engagement and is comparable to the costimulatory effects of CD28 [50] or TLR2 stimulation [17] previously described

Summary

Introduction

Pattern recognition receptors (PRR) are involved in the detection of microbial infections as well as tissue damage in mammals. They are expressed by a variety of cell types in which they sense danger signals through the recognition of pathogenassociated molecular patterns (PAMPs) or endogenous damageassociated molecular patterns (DAMPs) [1]. Recognition of cytosolic danger signals by other NLR, such as IPAF, NAIP5 and NALPs, leads to the formation of multiprotein complexes called inflammasomes, responsible for the activation of caspase-1, a protease required for processing and activation of the pro-inflammatory cytokines IL-1b and IL-18 [9]

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