Research Article

Neutrophil trails guide influenza-specific CD8+ T cells in the airways

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Science  04 Sep 2015:
Vol. 349, Issue 6252, aaa4352
DOI: 10.1126/science.aaa4352

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Neutrophils lay down the tracks

T cells constantly circulate throughout the body until an invading pathogen calls them into action. Microbes often cause localized infections, so how do T cells know where to go? Lim et al. explore this question in a mouse model of influenza infection and find that immune cells called neutrophils help guide the way (see the Perspective by Kiermaier and Sixt). Upon infection, neutrophils quickly traffic to the trachea. There, they lay down “tracks” enriched in proteins called chemokines, especially the chemokine CXCL12, which guide CD8+ T cells to the infected organ. Mice whose neutrophils could not lay down such tracks exhibited defects in CD8+ T cell recruitment and viral clearance.

Science, this issue 10.1126/science.aaa4352; see also p. 1055

Structured Abstract

INTRODUCTION

Influenza virus infects the epithelial cells that line the respiratory tract. Therefore, cytotoxic CD8+ T cells must traffic to this site to eliminate infected cells. The functions of antiviral CD8+ T cell effector at tissue sites require a successful and early innate immune response. Neutrophils are an immune cell subset that helps organs initiate and maintain immune reactions and shapes the overall immune response by signaling to multiple immune cell types, including T cells. Under most inflammatory conditions, neutrophils are the first cell type that crosses the blood vessel endothelium into the tissue, often preceding a subsequent wave of effector T cells. Although neutrophils are known to recruit T cells into infected sites during both bacterial and viral infections and in chronic inflammatory diseases, the molecular mechanisms that link neutrophil and T cell migration remain unknown.

RATIONALE

The chemokine receptor family is the most potent tissue-specific family of homing receptors for T cells and is subset-selective. Therefore, it is widely assumed that the distinct migratory properties and distribution patterns of different subsets of specialized T cells result from the differential expression of the chemokines and their receptors. Although this idea has been verified experimentally in some settings, multiple chemokine receptors expressed on the effector T cells and the redundancy in their signaling pathways suggest the presence of a more complex mechanism that can confer specificity and selectivity to T cell recruitment. Furthermore, less is known about how chemokines released from newly recruited leukocytes act together with the local chemokines produced within the inflamed tissue. To address this, we performed intravital multiphoton microscopy imaging of the influenza-infected mouse trachea and explored how neutrophil-derived chemokines cooperate with the tissue-specific inflammatory cues to finely control the recruitment of CD8+ T cells to the influenza-infected trachea.

RESULTS

Here, we show that optimal CD8+ T cell–mediated immune protection requires the early recruitment of neutrophils into influenza-infected trachea. In particular, the relative motility of virus-specific CD8+ T cells in the trachea was determined by their localization to the epithelium, which was governed by the presence of neutrophils during early infection. Both in vitro and in vivo imaging showed that migrating neutrophils leave behind long-lasting trails from their elongated uropods (a protrusion at the rear of a cell) that are prominently enriched in the chemokine CXCL12. We observed that CXCL12 derived from the epithelial cells remained close to the epithelium, whereas CXCL12 derived from neutrophils was the main source of CXCL12 in the tissue interstitium during infection. Experiments with granulocyte-specific CXCL12 conditionally depleted (knockout) mice and a CXCR4 antagonist revealed that CXCL12 derived from neutrophil trails is critical for virus-specific CD8+ T cell recruitment and antiviral effector functions.

CONCLUSION

The data presented here demonstrate that migrating neutrophils leave behind chemoattractant-containing trails, which result in the local accumulation of neutrophil-derived chemoattractant signals in inflamed tissues. As chemokines are small, diffusible molecules, perhaps these trails function to package the chemoattractant so that it can be preserved and survive severe mechanical perturbation during inflammation. Otherwise, the chemoattractant would be present only transiently, or it would immediately diffuse away from the site.

Neutrophils trails guide virus-specific CD8+ T cell migration.

In the influenza-infected trachea, tissue-infiltrating neutrophils (pink) deposit chemokine (CXCL12)–containing trails, which may serve like breadcrumbs or long-lasting chemokine depots to provide both chemotactic and haptotactic cues for efficient virus-specific CD8+ T cell migration and localization in the infected tissues.

Abstract

During viral infections, chemokines guide activated effector T cells to infection sites. However, the cells responsible for producing these chemokines and how such chemokines recruit T cells are unknown. Here, we show that the early recruitment of neutrophils into influenza-infected trachea is essential for CD8+ T cell–mediated immune protection in mice. We observed that migrating neutrophils leave behind long-lasting trails that are enriched in the chemokine CXCL12. Experiments with granulocyte-specific CXCL12 conditionally depleted mice and a CXCR4 antagonist revealed that CXCL12 derived from neutrophil trails is critical for virus-specific CD8+ T cell recruitment and effector functions. Collectively, these results suggest that neutrophils deposit long-lasting, chemokine-containing trails, which may provide both chemotactic and haptotactic cues for efficient CD8+ T cell migration and localization in influenza-infected tissues.

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