Neutrophil trails are essential for guiding T cells to the site of influenza infection

NIAID CEIRS | Research Publication Commentary

Lim, K., et al. Neutrophil trails guide influenza-specific CD8+ T cells in the airways. Science. (2015).

A well-functioning immune system is critical for protection against infection, and requires coordination of both the innate and adaptive immune response. The innate immune response, usually the first line of defense, consists of components that are active and ready to fight off infection. Neutrophils (a type of white blood cell and part of the innate immune response) are often the first immune cell to arrive at the site of infection. Neutrophils release a variety of small signaling molecules called chemokines which signal immune cell types like T cells to traffic to and eliminate the pathogen. Unlike the generalist innate immune response, the T cells are part of the adaptive immune response, and are designed to recognize and precisely fight a specific target. Although studies have shown that neutrophils recruit T cells to the site of infection, the molecular mechanisms underlying this process remained unknown until now.

Using immunofluorescence, live cell imaging, and flow cytometric analyses, Drs. Kihong Lim, Young-Min Hyun, and their colleague Dr. Topham from the New York Influenza Center for Excellence (NYICE), confirm that the arrival of neutrophils followed by the recruitment of CD8+ T cells at the site of infection are critical to clear influenza A virus infections in mice. The researchers go on to dissect the molecular mechanism and demonstrate that neutrophils create long trails of signaling molecules or chemokines, which are essential for guiding activated CD8+ T cells to the site of viral infection.

Of the six chemokines tested for their ability to guide T cells, only CXCL12 produced by neutrophils significantly induced CD8+ T cell migration, suggesting that T cell movements depend on CXCL12 signaling. Depletion of CXCL12 from neutrophils resulted in a significant delay in T cell recruitment to the infection site, even though CXCL12 is also produced by epithelial cells. These results show that neutrophils are essential to coordinate the innate and adaptive immune response in part because of their ability to guide T cells by using the chemokine CXCL12.

Next, the researchers investigated the method by which neutrophils deploy the CXCL12 signals. Live fluorescence imaging showed that during migration, neutrophils left behind membranous trails. Characterization of the neutrophil trails revealed that they were enriched with CXCL12. These observations show that migrating neutrophils leave behind chemoattractant-containing trails that provide a guide for T cells to navigate through inflamed tissues to the site of infection. The membranous trails trap the CXCL12, which otherwise would diffuse away very quickly.

Taken together, these results provide a greater understanding of the complexity of the human immune response and show how various components of the immune system must communicate and coordinate to fight an influenza infection.

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