Abstract
We previously showed that potassium channel tetramerization domain containing 9 (KCTD9) is aberrantly expressed in natural killer (NK) cells in patients with hepatitis B virus-associated acute-on-chronic liver failure and mice with experimental fulminant hepatitis. However, the mechanism underlying the regulation of NK cell function and fulminant hepatitis progression by KCTD9 is unknown. Here, we investigated the role of Kctd9 in regulation of early development, maturation, and function of NK cells using Kctd9-knockout mice. Compared to wild-type mice, Kctd9-deficient mice exhibited impaired NK cell lineage commitment, as evidenced by selective reduction in the refined NK progenitors, and incomplete NK cell maturation, as manifested by a higher proportion of CD11b− NK cells and a lower percentage of CD11b+ NK cells with high proliferative potential. Moreover, Kctd9-depleted NK cells displayed insufficient IFN-γ production, degranulation, and granzyme B production in response to cytokine stimulation, and attenuated cytotoxicity to tumor cells in vitro. The defect in NK cells was further supported by ameliorated liver damage and improved survival in Kctd9-deficient mice following murine hepatitis virus strain-3 (MHV-3) infection, which otherwise leads to immune-mediated fulminant hepatitis, a phenotype homologous to that caused by NK cell depletion in wild-type mice. Further investigation to identify the underlying mechanism revealed that Kctd9 deficiency hindered the expression of transcription factors, including Ets1, Nfil3, Eomes, and Id2 in NK cells. Collectively, our data reveal that Kctd9 acts as a novel regulator for NK cell commitment, maturation, and effector function.
Highlights
Natural killer (NK) cells are the major effector lymphocytes of the innate immune system in host defense against tumors and invading pathogens
We previously revealed the vital contribution of NK cells to liver damage, and the involvement of potassium channel tetramerization domain containing 9 (KCTD9) in NK cell function in viral fulminant hepatitis [22, 25]
Owing to the selective reduction of refined NKPs (rNKPs) as well as NK cells in bone marrow of Kctd9−/− mice, which rely on CD122 expression, we investigated whether Kctd9 regulates CD122 expression in NK cells
Summary
Natural killer (NK) cells are the major effector lymphocytes of the innate immune system in host defense against tumors and invading pathogens. NK cell development from common lymphoid progenitors (CLPs) occurs in the bone marrow (BM) through three stages: NK progenitors (NKPs), immature NK (iNK) cells, and mature NK (mNK) cells [1]. CD11b−CD27+NK cells express high levels of NKG2A and low levels of Ly49 receptors; CD11b+CD27+ and CD11b+CD27−NK cells, which are mainly located in the periphery, are equipped with a full repertoire of Ly49 receptors and cytotoxic potential [9]. Another discrepancy between iNK cells and mNK cells is the proliferative capacity, which occurs at a high potential in the immature stages and wanes upon further maturation. The proliferating potential during NK cell development continued after acquiring NK1.1 expression and before terminal maturation marked by high CD43 and KLRG1 expression [5, 10]
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