[Show abstract][Hide abstract] ABSTRACT: The early immune response to microbes is dominated by the recruitment of neutrophils whose primary function is to clear invading pathogens. However, there is emerging evidence that neutrophils play additional effector and regulatory roles. The present study demonstrates that human neutrophils assume Ag cross-presenting functions and suggests a plausible scenario for the local generation of APC-like neutrophils through the mobilization of unconventional T cells in response to microbial metabolites. Vγ9/Vδ2 T cells and mucosal-associated invariant T cells are abundant in blood, inflamed tissues, and mucosal barriers. In this study, both human cell types responded rapidly to neutrophils after phagocytosis of Gram-positive and Gram-negative bacteria producing the corresponding ligands, and in turn mediated the differentiation of neutrophils into APCs for both CD4(+) and CD8(+) T cells through secretion of GM-CSF, IFN-γ, and TNF-α. In patients with acute sepsis, circulating neutrophils displayed a similar APC-like phenotype and readily processed soluble proteins for cross-presentation of antigenic peptides to CD8(+) T cells, at a time when peripheral Vγ9/Vδ2 T cells were highly activated. Our findings indicate that unconventional T cells represent key controllers of neutrophil-driven innate and adaptive responses to a broad range of pathogens.
Journal of immunology (Baltimore, Md. : 1950). 08/2014;
[Show abstract][Hide abstract] ABSTRACT: It has recently been established that neutrophils, the most abundant leukocytes, are capable of changes in gene expression during inflammatory responses. However, changes in the transcriptome as the neutrophil leaves the bone marrow have yet to be described. We hypothesized that neutrophils are transcriptionally active cells that alter their gene expression profiles as they migrate into the vasculature and then into inflamed tissues. Our goal was to provide an overview of how the neutrophil's transcriptome changes as they migrate through different compartments using microarray and bio-informatic approaches. Our study demonstrates that neutrophils are highly plastic cells where normal environmental cues result in a site-specific neutrophil transcriptome. We demonstrate that neutrophil genes undergo one of four distinct expression change patterns as they move from bone marrow through the circulation to sites of inflammation: (i) continuously increasing; (ii) continuously decreasing; (iii) a down-up-down; and (iv) an up-down-up pattern. Additionally, we demonstrate that the neutrophil migration signaling network and the balance between anti-apoptotic and pro-apoptotic signaling are two of the main regulatory mechanisms that change as the neutrophil transits through compartments.Cellular & Molecular Immunology advance online publication, 9 June 2014; doi:10.1038/cmi.2014.37.
[Show abstract][Hide abstract] ABSTRACT: Of all cells implicated in the pathology of rheumatoid arthritis (RA), neutrophils possess the greatest cytotoxic potential, owing to their ability to release degradative enzymes and reactive oxygen species. Neutrophils also contribute to the cytokine and chemokine cascades that accompany inflammation, and regulate immune responses via cell-cell interactions. Emerging evidence suggests that neutrophils also have a previously unrecognised role in autoimmune diseases: neutrophils can release neutrophil extracellular traps (NETs) containing chromatin associated with granule enzymes, which not only kill extracellular microorganisms but also provide a source of autoantigens. For example, citrullinated proteins that can act as neoepitopes in loss of immune tolerance are generated by peptidylarginine deiminases, which replace arginine with citrulline residues, within neutrophils. Indeed, antibodies to citrullinated proteins can be detected before the onset of symptoms in patients with RA, and are predictive of erosive disease. Neutrophils from patients with RA have an increased tendency to form NETs containing citrullinated proteins, and sera from such patients contain autoantibodies that recognize these proteins. Thus, in addition to their cytotoxic and immunoregulatory role in RA, neutrophils may be a source of the autoantigens that drive the autoimmune processes underlying this disease.
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