We need to talk about neutrophils

Over the past 15 years, our understanding of neutrophils has undergone an enormous shift – particularly for those of us who work in adaptive immunology. For many of us, neutrophils pre-2005 were simple cells, indiscriminate killers which shot first and asked questions never. They responded rapidly and died within hours, meaning we did not consider them in our models of complicated adaptive immunity or of chronic inflammatory disease.

Opinions began to change following the publication of some beautiful studies describing many features of neutrophilic inflammation, which are highly relevant to adaptive immune responses. We now understand that neutrophils do not only move into tissues following an inflammatory trigger, but also appear in the lymphatics. Neutrophils began to be observed in lymph nodes from a few hours post-immunization or inflammatory trigger [1, 2] – and, excitingly, a small population of neutrophils, which circulates through the lymphatics at steady state, was also found [3].

Direct interactions between neutrophils and lymphocytes were also observed [4], and descriptions of both direct presentation [5] and cross-presentation [6] of antigen by the neutrophils opened a new area of study. In vivo, observations of neutrophils interacting with dendritic cells in the intestine were described as a feature of chronic autoimmune disease [7], and T cells in the lung following trails of chemokines left behind by neutrophil extravasation were described during infection [8]. The importance of neutrophils in suppressing T-cell populations in cancer – thus driving metastasis – was discussed [9]. These studies and many others reveal the complexity of innate-adaptive immune interactions, showing as they do both activatory and suppressive outcomes of neutrophil–lymphocyte contact. We are only just beginning now to understand this complexity.

More recently, mechanistic analyses have begun to decipher the pathways through which these effects occur. Cathelicidin, a neutrophil peptide released by NETosis and degranulation, chemo-attracts T cells [10] and promotes Th17 differentiation [11]. Likewise, the release of neutrophil elastase strongly promotes Th17 responses [12], while the alpha-defensins have multiple pro-inflammatory effects on DC and T cells including chemo-attraction and enhanced cytokine release (reviewed in the study [13]). Neutrophils can also suppress lymphocyte activation through the expression of PDL1 [14] and the release of arginase-1 [15].

Taking all of these observations together, there are two conclusions we can draw: firstly, that we need to consider the interaction of neutrophils with T cells and B cells as a phenomenon which frequently occurs and which has the power to alter lymphocyte phenotype and behaviour, both in lymph nodes and in tissues. Secondly, the realization that neutrophil life span may be much longer than previously considered [16], and the observation of neutrophils persisting long term in chronic human inflammatory disease [17], means that we need to examine the importance of these interactions in chronic disease and in acute infections.

Now, we have brought together this review series to showcase the current understanding of neutrophil-adaptive immune interactions in a range of diseases and in a number of tissues. In this series, Bert et al. [18] discuss how neutrophils may affect T-cell differentiation in pregnancy, a situation in which the outcome is suppressive and has particular effects on T regulatory cells. Laurence Lok and Menna Clatworthy [19] then provide an up-to-the-moment examination of the lymph node neutrophil and its influence on the development of adaptive immune responses. An evaluation of neutrophil involvement with B cells in the rheumatic joint by Utsa Karmakar and Sonja Vermeren [20] emphasizes the importance of neutrophil extracellular traps in inflammatory disease. Finally, two papers describe the importance of neutrophilia in human inflammatory and chronic diseases, with Mincham et al. [21] group discussing the inflamed lung and Egle Kvedaraite [22] the intestine. In these tissues, chronic neutrophilia has long been observed during disease and its impact on immunity, immunopathology and potential therapeutic strategies is enormous.

Together, these papers bring us to the cutting edge of understanding how neutrophilia affects adaptive immunity. The advent of new strategies and technologies to observe and decipher the behaviour of neutrophils in human tissues means we can expect many more exciting developments to come.

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