Phagocytic neutrophils cross-present antigen

In this issue of Blood, Beauvillain and colleagues show that murine as well as human neutrophils are capable of cross-presenting exogenous antigens to CD8⁺ T cells.

Neutrophils are the main inflammatory cells responsible for pathogen killing at sites of infection. Beauvillain and colleagues show that neutrophils can also acquire antigen at the site of inflammation, migrate to lymphoid organs, and present the antigen to naive CD8 cells in a process called cross-presentation.

Cross-presentation—the ability of antigen-presenting cells (APCs) to take up, process, and present extracellular antigens within the MHC class I pathway, resulting in the induction of antigen-specific, cytotoxic CD8⁺ T cells—is a process important for immunity against tumors, viruses, and bacteria that are not taken up by APCs (for a review, see Shen et al ¹ ). Cross-presentation was demonstrated primarily in dendritic cells, which phagocytose apoptotic particles using specialized receptors or by pinocytosis of extracellular proteins.^2,3  Other APCs described with limited ability to cross-present are macrophages, B cells, and liver sinusoidal endothelial cells.¹ 

Neutrophils are the most frequently occurring leukocytes in the body (50%-65%). Every day, our bone marrow releases approximately 10¹¹ neutrophils into circulation. Upon local release of proinflammatory mediators (eg, IL-1, TNFα) from stromal cells, neutrophils rapidly migrate toward the infected site.⁴  Thus, they are among the first cells to reach the affected tissue in high numbers. As part of innate immunity, their main function is (1) to orchestrate subsequent inflammatory processes, such as monocyte recruitment, and (2) to phagocytose microorganisms and efficiently eliminate them.⁴  To do so, they are equipped with granules containing various enzymes. No other cell of the body is equally equipped with comparable machinery designed for pathogen killing.

Neutrophils are cells with a very short life span. After contact with pathogens, their viability is prolonged, but ultimately, all neutrophils die of programmed cell death within a few hours or days. Prior studies suggested that apoptotic neutrophils containing foreign protein can be phagocytosed by dendritic cells (DCs), leading to cross-presentation of this exogeneous antigen.¹  Considering the high number of apoptotic neutrophils with antigen present in inflamed tissue early on, this indirect way of activating adaptive immunity seems reasonable.

Beauvillain and colleagues show for the first time that neutrophils can directly cross-prime T cells themselves. They demonstrate that neutrophils can function as antigen-presenting cells: they rapidly cross-present antigen (within a few hours) as potently as macrophages, but not as strongly as dendritic cells. Especially in light of the speed and the large number of neutrophils in inflammation, this process may be highly relevant for T-cell priming in vivo. The present findings raise a number of interesting questions: in vivo, are the numbers of neutrophils carrying antigen and migrating to draining lymph nodes sufficient to induce efficient CD8 priming? What about their short life span as compared with the need to migrate to the lymph node to encounter naive T cells and cross-present? Can neutrophils be utilized as targets to induce protective CD8 responses against tumors? As suggested by the report of Beauvillain and colleagues, cross-priming by neutrophils also occurs in the absence of CD4 help—a finding that will have to be confirmed. These and more interesting questions, including whether this process is relevant for real disease models, will have to be answered in the near future.