TREM2 Promotes Natural Killer Cell Development in CD3-CD122+NK1.1+ pNK Cells

Abstract

Background: Triggering receptor expressed on myeloid cells 2 (TREM2) signaling is considered to regulate anti-inflammatory responses in macrophages, dendritic cell maturation, osteoclast development, induction of obesity, and Alzheimer’s disease pathogenesis. However, little is known regarding the effect of TREM2 on natural killer (NK) cells.Results: Here, we demonstrated for the first time that CD3-CD122+NK1.1+ precursor NK (pNK) cells expressed TREM2 and their population increased in TREM2-overexpressing transgenic (TREM2-TG) mice compared with that in female C57BL/6J wild type (WT) mice. Both NK cell-activating receptors and NK cell-associated genes were expressed at higher levels in various tissues of TREM2-TG mice than in WT mice. In addition, bone marrow-derived hematopoietic stem cells (HSCs) of TREM2-TG mice (TG-HSCs) successfully differentiated into NK cells in vitro, with a higher yield from TG-HSCs than from WT-HSCs. In contrast, TREM2 signaling inhibition by TREM2-Ig or a phosphatidylinositol 3-kinase (PI3K) inhibitor affected the expression of the NK cell receptor repertoire and decreased the expression levels of NK cell-associated genes, resulting in significant impairment of NK cell differentiation. Moreover, in melanoma-bearing WT mice, injection of bone marrow cells from TREM2-TG mice exerted greater antitumor effects than that with cells from WT control mice.Conclusions: Collectively, our data clearly showed that TREM2 promoted NK cell development and tumor regression, suggesting TREM2 as a new candidate for cancer immunotherapy.

The emerging role of triggering receptor expressed on myeloid cell-2 in malignant tumor

“…Compared with wild-type mice, hematopoietic stem cells from TREM2 overexpressed mice showed a higher tendency to differentiate into NK cells and showed increasing expression of NK cell-activated receptors and NK cell-related genes. The transfer of bone marrow cells from TREM2 overexpressed mice to tumor-bearing mice significantly restrains tumor progression [54]. These observations suggest that TREM2 enhances the differentiation and function of NK cells, and through this mechanism, TREM2 may fulfil an antitumor role.…”

“…For example, targeting TREM2 in macrophages may acquire ideal efficacy since TREM2 can enhance immunosuppressive functions of these cells. However, in NK cells, targeting TREM2 may impede the maturation of NK cells and their ability to kill tumor cells [54]. More related studies are needed to confirm exactly how TREM2 works in tumors, and clinical trials are urgently needed to bring TREM2 to the clinic as soon as possible, thus contributing to new strategies for tumor immunotherapy.…”