Abstract
Natural killer (NK) cells are members of the innate lymphoid cells group 1 (ILC1s), which play a critical role in innate host defense against viruses and malignancies. While many studies have examined the role of circulating peripheral blood (PB) CD56+ NK cells, little is known about the resident CD56+ cell population. Therefore, matched CD56+ cells from nasal lavage fluid (NLF) and PB of smokers and non-smokers were compared phenotypically, via flow cytometry, and functionally, via NK-cell specific gene expression. NLF and PB CD56+ cells had similar expression of CD56, but differentially expressed tissue residency (CD69 and CD103) and cytotoxicity (CD16) markers. In addition, NLF CD56dim cells expressed lower levels of cytotoxicity-associated genes, perforin (PRF1) and granzyme B (GZMB), and increased levels of cytokines and cell signaling molecules, TRAIL, IFNGR2, and IL8, as compared to PB CD56dim cells. In smokers, ITGA2 was downregulated in NLF CD56dim cells, while markers of cytotoxic function were primarily downregulated in PB CD56dim NK cells. Overall, NLF CD56dim cells are a unique cell population that likely play a role in orchestrating innate immune responses in the nasal cavity, which is distinct from their role as a non-antigen-restricted cytotoxic CD56dim lymphocytes in the PB.
Highlights
The majority of what is known about Natural killer (NK) cells is derived from studies on peripheral blood (PB) and lymphoid NK cells as they are highly abundant and easy to access
In order to further characterize these nasal CD56+ cells based on their gene expression profiles, it was necessary to enrich the nasal lavage fluid (NLF) population for the specific cell population of interest, CD56+ NK cells
To determine more broadly phenotypic differences in NLF and PB CD56+ NK/ILC1 cells, we developed a gene expression panel, consisting of 64 genes related to NK cell function, including surface markers/receptors (n = 28 genes), mediators (n = 16 genes), signaling (n = 14 genes), markers for other potential cell populations, and housekeeping genes (n = 4 genes) (Supplementary Table 2). 7 genes were more robustly expressed in the NLF CD56+ NK/ILC1 cells than PB CD56+ NK/ILC1 cells (Table 1)
Summary
The majority of what is known about NK cells is derived from studies on peripheral blood (PB) and lymphoid NK cells as they are highly abundant and easy to access. We have demonstrated that superficial scrape biopsies of the nasal mucosa contain CD45+CD56+ cells, but based on histological evaluations, it is unclear whether these cells are embedded in the tissue or are collected as part of leukocytes populations patrolling the nasal mucosa[20] It is unknown how nasal resident CD56+ cells differ from peripheral blood NK cells and to what extend these cells express CD16 and/or CD69 and CD103, potentially differentiating them as NK cells or ieILC1s. Cigarette smoke is known to suppress innate immune functions[21] and we have previously shown that CD56+ cells in the nasal lavage of smokers show reduced markers of cytotoxic activation following viral infection[16,22]. Overall results suggest that nasal resident CD56+ cells are a unique cell population, resemble previously described ieILC1s, are phenotypically and functionally distinct from PB and lung resident NK cells, and express markers that are indicative of a primarily immune orchestrating role in the nasal mucosa
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