Type 2 and Type 17 Invariant Natural Killer T Cells Contribute to Local Eosinophilic and Neutrophilic Inflammation and Their Function Is Regulated by Mucosal Microenvironment in Nasal Polyps

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by heterogeneous inflammatory endotypes of unknown etiology. Invariant natural killer T (iNKT) cells are multifunctional innate T cells that exhibit Th1-, Th2-, and Th17-like characteristics. We investigated functional relationships between iNKT cells and inflammatory subtypes of CRSwNP. Eighty patients with CRSwNP and thirty-two control subjects were recruited in this study. Flow cytometry was used to analyze the frequencies and functions of iNKT cells and their subsets in peripheral blood mononuclear cells (PBMCs) and tissues. Polyp tissue homogenates were used to study the multifunctionality of iNKT cells. iNKT cells were significantly increased in polyps (0.41%) than in control mucosa (0.12%). iNKT cells were determined in the paucigranunlocytic (n=20), eosinophilic (n=22), neutrophilic (n=23), and mixed granulocytic (n=13) phenotypes of CRSwNP. The percentages of iNKT cells and HLA-DR+PD-1+ subsets were lower in eosinophilic or mixed granulocytic polyps than those of other phenotypes. iNKT cells and subsets were enriched in polyp tissues than in matched PBMCs. The evaluation of surface markers, transcription factors, and signature cytokines indicated that the frequencies of iNKT2 and iNKT17 subsets were significantly increased in eosinophilic and neutrophilic polyps, respectively, than in the paucigranulocytic group. Moreover, the production of type 2 (partially dependent on IL-7) and type 17 (partially dependent on IL-23) iNKT cells could be stimulated by eosinophilic and neutrophilic homogenates, respectively. Our study revealed that type 2 and type 17 iNKT cells were involved in eosinophilic and neutrophilic inflammation, respectively, in CRSwNP, while different inflammatory microenvironments could modulate the functions of iNKT cells, suggesting a role of iNKT cells in feedback mechanisms and local inflammation.