Cytokine-induced memory-like natural killer cells in systemic lupus erythematosus patients.

Abstract

BACKGROUND: Natural killer (NK) cell abnormalities may contribute to the pathogenesis of systemic lupus erythematosus (SLE). Interleukin (IL)-15, an immunoregulatory cytokine crucial for NK survival, is overexpressed in SLE patients. Cytokine-induced memory-like (CIML) NK cells, which are NK cells pre-activated with short-term IL-12+IL-15+IL-18 followed by incubation with low-dose IL-15 for 1-2 weeks, exhibit enhanced NK effector function upon re-stimulation. METHODS: We collected blood samples from 54 patients with SLE and 38 healthy volunteers. Extended IL-15 stimulation of peripheral blood mononuclear cells (PBMCs) was performed. Surface marker analysis, IFN-γ, TNF-α production, and cytotoxicity evaluation were conducted. Next, we generated CIML NK cells by culturing PBMCs with IL-12+IL-15+IL-18. The influence of short-term and long-term IL-15 treatment on CIML NK cells was assessed. Finally, we examined the effect of re-stimulation with IL-12+IL-15+IL-18 on CIML NK cells from SLE patients and healthy controls. Cytotoxicity, CD107a degranulation, and surface marker expression were analyzed. RESULTS: We found that 1. The percentage of CD3-CD56+ NK cells was initially decreased in SLE patients compared with controls, but was enhanced after long-term IL-15 incubation; 2. Long-term IL-15 stimulation facilitated the conversion from CD3-CD56dim to CD3-CD56bright NK cells; 3. CIML NK cells were successfully generated in SLE patients, showing increased percentages of CD3-CD56+ and CD3- CD56bright NK cells and a concomitant decrease in CD3-CD56dim NK cells; 4. SLE CIML NK cells showed decreased IFN-γ, CD69, CD94, NKG2A, NKG2C, NKP30, NKP44, NKP46, and granzyme B expression compared with healthy controls; 5. On day 8, re-stimulation with IL-12+IL-15+IL-18 further enhanced the expression of IFN-γ, CD69, CD94, NKG2A, perforin, and granzyme B expression on SLE CIML NK cells; 6. Granzyme B expression in SLE CIML NK cells was higher on day 8 than on day 15. CONCLUSION: Our findings revealed phenotypic differences and functional deficiencies in SLE CIML NK cells. Further investigation into the role of SLE CIML NK cells in providing antiviral and anti-tumor responses is warranted. CLINICAL TRIAL NUMBER: Not applicable.