Expression regulation of co-inhibitory molecules on human natural killer cells in response to cytokine stimulations
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Published on: February 22, 2020
Haoyu Sun1, Cheng Sun, Weihua Xiao
1Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
Abstract:
Co-inhibitory molecules have become the key targets in cancer immunotherapy with the strategy of blocking immune checkpoints to reverse the pathogenic regulation of T cells. However, their expression regulations in NK cells, the most important innate immune cells against tumor, remain largely undefined. In this study, we showed that the expressions of co-inhibitors on NK cells, including LAG-3, PD-1, and TIGIT, are differently regulated by cytokines IL-10, IL-12, IL-15, IFN-α, and TGF-β. Among the tested cytokines, IL-12 is the most powerful inducer of LAG-3, and TGF-β is the strongest suppresser of PD-1. Notably, the expression of these co-inhibitors responds to the time course of stimulus progressively. Together, these findings illustrated that the co-inhibitors on NK cells express differently in response to cytokine stimulations of IL-10, IL-12, IL-15, IFN-α, and TGF-β, providing an initial information on the expression regulation of co-inhibitors in human NK cells.
Insights
Cytokines IL-10, IL-12, IL-15, IFN-α, and TGF-β differentially regulate co-inhibitory molecule expression on natural killer (NK) cells. This study provides initial insights into co-inhibitor expression on human NK cells in response to cytokine stimulation.
Area of Science:
- Immunology
- Cancer Biology
- Cellular and Molecular Immunology
Background:
- Co-inhibitory molecules are key targets in cancer immunotherapy, aiming to reverse T cell dysfunction.
- Understanding co-inhibitory molecule regulation on natural killer (NK) cells is crucial, as they are vital innate immune cells against tumors.
- The precise regulation of these molecules on NK cells remains largely undefined.
Purpose of the Study:
- To investigate the differential regulation of co-inhibitory molecules (LAG-3, PD-1, TIGIT) on human NK cells by various cytokines.
- To identify specific cytokines that induce or suppress the expression of these co-inhibitory molecules.
- To characterize the temporal dynamics of co-inhibitory molecule expression following cytokine stimulation.
Main Methods:
- Human NK cells were stimulated with a panel of cytokines: IL-10, IL-12, IL-15, IFN-α, and TGF-β.
- Expression levels of co-inhibitory molecules, including Lymphocyte-Activation Gene 3 (LAG-3), Programmed cell Death protein 1 (PD-1), and T cell immunoreceptor with Ig and ITIM domains (TIGIT), were analyzed.
- Time-course experiments were conducted to assess the progressive response to cytokine stimuli.
Main Results:
- Cytokines IL-10, IL-12, IL-15, IFN-α, and TGF-β differentially modulated the expression of LAG-3, PD-1, and TIGIT on NK cells.
- Interleukin-12 (IL-12) was identified as the most potent inducer of LAG-3 expression.
- Transforming growth factor-beta (TGF-β) demonstrated the strongest suppressive effect on PD-1 expression.
- Co-inhibitor expression exhibited a progressive response over time following cytokine stimulation.
Conclusions:
- The expression of co-inhibitory molecules on human NK cells is distinctly regulated by specific cytokines.
- IL-12 and TGF-β play significant roles in modulating LAG-3 and PD-1 expression, respectively.
- These findings offer foundational information on the cytokine-mediated regulation of co-inhibitory molecules in human NK cells, relevant for cancer immunotherapy strategies.
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