Recently, researchers from the University of Science and Technology of China and Anhui Medical University have confirmed in new research that insulin-like growth factor (IGF-1) is an important regulator of human natural killer cell (NK cell) development and function. Related papers were published in the journal Nature Communications on February 12.
Professor Haiming Wei and Zhigang Tian of the University of Science and Technology of China are co-corresponding authors of this paper. The former's main research interests are the relationship between NK cell subsets and the occurrence and development of important diseases, and tumor biotherapy techniques based on innate immunity. The latter is mainly engaged in the research of NK cell biology, liver immunology, and the development of new biological treatment technologies and products based on NK cells.
NK cells are a special subset of lymphocytes that play a central role in innate immunity. In recent years, more and more studies in mice and humans have shown that NK cells also play an important role in the adaptive immune response. The cytotoxic effect of NK cells is essential for defense against various processes such as pathogens and tumors. The cytotoxic mechanism of NK cells is mainly mediated by perforin and granzyme, both of which are necessary effector molecules for NK cell cytotoxic activity. After granule exocytosis, perforin promotes granzyme into the cytosol of target cells, cleaves a large number of substrates such as caspases, and rapidly induces apoptosis.
According to the CD65 density on the cell surface, human NK cells can be divided into two subpopulations, CD56bright and CD56dim; these cell subpopulations differ in function, phenotype, and tissue location. More than 90% of peripheral blood NK (pNK) cells are CD56dim subpopulations, which express high levels of perforin, CD16, and killer Ig-like receptors (KIR). The CD56bright cell subpopulation is rare in the blood, but mainly exists in lymph nodes, inflammatory tissues and decidua, expressing low levels of perforin and KIR. In contrast, the CD56dim subpopulation is highly cytotoxic and preferentially produces cytokines after identifying target cells. However, the mechanism behind these cytotoxic differences in human NK cells is not yet clear.
In in vitro experiments, studies have found that cytokines play an important role in the development of NK cells. In the presence of only cytokines, hematopoietic progenitor cells derived from bone marrow or cord blood can be differentiated into human NK cells. Various combinations of cytokines have been shown to support the proliferation and differentiation of human CD34 + hematopoietic stem cells (HSCs) into mature NK cells.
IGF-1, also known as somatomedin C, is an important endocrine regulatory factor for growth and development under physiological conditions. In addition to this important function, IGF-1 also plays an important role in regulating immunity and inflammation. There is increasing evidence that IGF-1 also regulates the hematopoiesis and direct effector functions of cells in the innate and acquired immune systems. IGF-1 also plays a complex regulatory role in adult hematopoietic progenitor cells and can stimulate the proliferation of bone marrow and erythrocyte progenitor cells. In addition, IGF-1 also interacts with IGF-1R to regulate various aspects of T cell, B cell, and monocyte function. Almost all immune systems, including T cells, B cells, peripheral blood mononuclear cells (PBMCs) and NK cells, express IGF-1R, and are therefore susceptible to IGF-1. However, the role of IGF-1 in NK cell development and function is currently unclear.
In this article, the researchers confirmed that IGF-1 can promote the differentiation of human CD34 + HSCs into NK cells and increase the cytotoxic activity of NK cells. Differential expression of endogenous IGF-1 can lead to differences in cytotoxic activity of human primary NK cells. In addition, the researchers confirmed that in human NK cells, endogenous IGF-1 is regulated by miR-483-3p. When miR-483-3p is overexpressed, it can cause an effect similar to that of IGF-1 blockade, resulting in decreased NK cell cytotoxic activity. The inhibition of miR-483-3p has the opposite effect.
These findings indicate that IGF-1 plays an important positive regulatory role in human NK cell development and cytotoxicity. The regulation of endogenous IGF-1 by miR-483-3p is essential for the cytotoxic activity of human NK cells. The new research provides an understanding of the new mechanism of human NK cell biology. Given the importance of NK cells in immunotherapy, this information may provide new opportunities for therapeutically promoting or limiting NK cell cytotoxicity.
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