Nociceptive sensory neurons promote CD8 T cell responses to HSV-1 infection

Jessica Filtjens,Sandrine Henri,Bernard Malissen,Guillaume Hoeffel,Jordi Gouilly,Anais Roger,Francis R Carbone,Sophie Ugolini,Laura K Mackay,Clara Daher,Elisabeth Wieduwild,Claerwen M Jones,Linda Quatrini,Guilhaume Debroas,Aziz Moqrich,Rafaëlle Rossignol

doi:10.1038/s41467-021-22841-6

Abstract

Host protection against cutaneous herpes simplex virus 1 (HSV-1) infection relies on the induction of a robust adaptive immune response. Here, we show that Nav1.8+ sensory neurons, which are involved in pain perception, control the magnitude of CD8 T cell priming and expansion in HSV-1-infected mice. The ablation of Nav1.8-expressing sensory neurons is associated with extensive skin lesions characterized by enhanced inflammatory cytokine and chemokine production. Mechanistically, Nav1.8+ sensory neurons are required for the downregulation of neutrophil infiltration in the skin after viral clearance to limit the severity of tissue damage and restore skin homeostasis, as well as for eliciting robust CD8 T cell priming in skin-draining lymph nodes by controlling dendritic cell responses. Collectively, our data reveal an important role for the sensory nervous system in regulating both innate and adaptive immune responses to viral infection, thereby opening up possibilities for new therapeutic strategies.

Highlights

Host protection against cutaneous herpes simplex virus 1 (HSV-1) infection relies on the induction of a robust adaptive immune response
Viral titres in the skin two days post infection were similar (Fig. 1a), showing that the primary phase of viral replication was not affected by the deletion of the thymidine kinase (TK)-encoding gene
These data were confirmed by flow cytometry analysis, which showed that CD45+ haematopoietic cells in the skin, lymph nodes (LN) and spleen did not express the fluorescent marker (Supplementary Fig. 1a)

Summary

Introduction

Host protection against cutaneous herpes simplex virus 1 (HSV-1) infection relies on the induction of a robust adaptive immune response. During inflammatory processes and infections, pathogen-derived molecules, lipids and immune cell-derived mediators act on the peripheral nerve terminals of nociceptive sensory neurons[7] These mediators include ATP, prostaglandins and leukotrienes, bradykinin, histamine, growth factors and cytokines[8]. The absence of certain neuron subpopulations in Nav1.8-DTA mice may, theoretically, have a direct effect on the rate of viral replication during the secondary growth phase, with possible consequences for the quality or magnitude of the immune response induced We overcame this potential bias, which would otherwise have made it impossible to assess the direct role of neurons in controlling the immune response, by generating a mutant form of the virus capable of replicating in skin epithelial cells, but not in neurons

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