Contribution of Regulatory T Cells in Nucleotide-Binding Oligomerization Domain 2 Response to Influenza Virus Infection.

Benoit Egarnes,Jean Gosselin

doi:10.3389/fimmu.2018.00132

Abstract

Influenza A virus (IAV) is recognized to cause severe pulmonary illnesses in humans, particularly in elderly and children. One of the features associated with IAV infection is an excessive lung inflammation due to an uncontrolled immune response. The nucleotide-binding oligomerization domain 2 (NOD2) receptor is known to recognize ssRNA viruses such as IAV, but its role in the inflammatory process during viral infections remains to be clarified. In a previous report, we have shown that activation of NOD2 with muramyl dipeptide (MDP) significantly reduces both viral loads and lung inflammation and also improves pulmonary function during IAV infection. These findings prompted us to further investigate whether NOD2 receptor may contribute to regulate inflammation during viral infection. In the present study, we show that administration of MDP to mice infected with IAV stimulates the migration of regulatory T (Treg) cells to the lungs. Such a presence of Treg cells was also accompanied with a reduction of neutrophils in the lungs during IAV infection, which correlated, with a significant decrease of Th17 cells. In our model, Treg cell recruitment is dependent of CXCL12 and CCL5 chemokines. Moreover, we show that the presence of Ly6Clow patrolling monocytes is required for Treg cells mobilization to the lung of mice treated with MDP. In fact, following monocyte depletion by administration of clodronate liposome, mobilization of Treg cells to the lungs of treated mice was found to occur when circulating Ly6Clow monocytes begin to reemerge. In addition, we also detected an increased production of TGF-β, a cytokine contributing to Treg activity when blood Ly6Clow monocytes are restored. Together, our results demonstrate that MDP treatment can promote an anti-inflammatory environment through the mobilization of Treg cells to the lung, a mechanism that requires the presence of Ly6Clow monocytes during IAV infection. Overall, our results suggest that activation of NOD2 receptor could be an appealing approach to control pulmonary inflammation in patients infected with IAV.

Highlights

Influenza virus is responsible for annual epidemic infection around the world causing severe morbidity, mostly among elderly, children, and people with chronic pulmonary disease
Since we previously reported that administration of muramyl dipeptide (MDP) to mice infected with influenza A virus (IAV) reduces lung inflammation [32], we first wanted to determine if such effects of MDP treatment could lead to the mobilization of Treg cells in lungs of IAV-infected mice
We have shown that nucleotide-binding oligomerization domain 2 (NOD2) triggering by MDP treatment improves mice pulmonary function during IAV infection, suggesting that NOD2 pathway may contribute to regulate lung inflammation [32]

Summary

Introduction

Influenza virus is responsible for annual epidemic infection around the world causing severe morbidity, mostly among elderly, children, and people with chronic pulmonary disease. Tregs are recognized as CD4+ CD25+ T cells which express the transcription factor FoxP3 [5, 6] They play a central role in the maintenance of immunological tolerance and are known to maintain self-tolerance and prevent autoimmune and chronic inflammatory diseases [7,8,9]. Tregs appear essential to clear influenza virus infection in neonatal mice [16], as their depletion results in enhanced lung inflammatory response to IAV infection. In line with these observations, it was demonstrated that Tregs contribute to the resolution of lung inflammation after influenza virus infection [17]. It was shown that administration of Treg neutralizing antibodies to infected mice has no significant effects on body weight loss, mortality, and viral clearance, suggesting that this cell population has a limited role in controlling IAV infection

Methods

Results

Conclusion