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. 2020 Apr 3;10(1):5858.
doi: 10.1038/s41598-020-62654-z.

Phenotypic and functional characterization of natural killer cells in rheumatoid arthritis-regulation with interleukin-15

Syh-Jae Lin #  1 , Chien-Ya Hsu #  2 , Ming-Ling Kuo  2   3   4 , Pei-Tzu Lee  2 , Hsiu-Shan Hsiao  2 , Ji-Yih Chen  5
Affiliations

Phenotypic and functional characterization of natural killer cells in rheumatoid arthritis-regulation with interleukin-15

Syh-Jae Lin et al. Sci Rep. .

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and joint destruction. Previous studies have shown that natural killer (NK) cells may play an important role in the pathogenesis of RA. Interleukin (IL)-15, a pro-inflammatory cytokine which induces proliferation and differentiation of NK cells, is overexpressed in RA. In this present study, we examine various NKRs and adhesion molecule expression on NK cells from RA patients and their response to IL-15 stimulation. We also sought to study cytokine-induced memory-like (CIML) NK cells in RA patients. We established that 1. RA patients had higher NK cell percentages in peripheral blood and their serum IL-15 levels were higher compared to healthy volunteers; 2. NK cells from RA patients showed lower NKp46 expression and an impaired CD69 response to IL-15; 3. NK cells from RA patients showed higher CD158b and CD158e expression but lower CD62L expression; 4. exogenous IL-15 up-regulated CD69, CD158b, CD158e but down-regulated NKp46 and CD62L expression in RA; 5. As to CIML NK cells, restimulation - induced NK cytotoxicity and IFN-γ production was impaired in RA patients, 6. Reduced NKp46, perforin, and granzyme B expression on NK cells was found in RA patients with bone deformity and erosion, 7. RA disease activity (DAS28) showed inverse correlation with the percentages of CD56+CD3- NK cells, and NKp46 and perforin expression on NK cells, respectively. Taken together, our study demonstrated differential expression of various NK receptors in RA patients. NKp46, CD158e, and perforin expression on NK cells may serve as markers of RA severity.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Comparison of (a) the percentages of peripheral blood CD56+CD3− NK cells from RA patients (n = 32) and healthy volunteers (n = 20) under the influence of IL-15. MNCs were stimulated with or without IL-15 (10 ng/mL) for 18 hours and further stained by anti-CD3 and anti-CD56 antibodies and assessed by flow cytometry, and (b) serum IL-15 concentration of healthy volunteers (n = 20) and RA patients (n = 32). Data was presented as percent expression (%) ± SEM. ** p < 0.01, RA patients compare with healthy volunteers (Normal).
Figure 2
Figure 2
NKp46 (a), CD69 (b) CD158b (c), CD158e (d), and CD62L (e) expression of CD56+CD3− NK cells from RA patients and healthy volunteers(Normal) with or without exogenous IL-15. MNCs were stimulated with or without IL-15 (10 ng/mL) for 18 hours, and further stained by anti-CD3 and anti-CD56 antibodies. CD56+CD3− NK cells were gated and surface markers (NKp46, CD69, CD158b, CD158e, CD62L) expression were analyzed by flow cytometry. Data was presented as percent expression (%) ± SEM. ((a) healthy volunteers n = 17, RA n = 32 (b) healthy volunteers n = 20, RA n = 32 (c) healthy volunteers n = 7, RA n = 32 (d) healthy volunteers, n = 8, RA, n = 11 (e) healthy volunteers, n = 20, RA, n = 21). *means p < 0.05, **p < 0.01.
Figure 3
Figure 3
(a) K562 cytotoxicity, (b)IFN-γ secretion, (c) CD69 expression (d) NKG2A expression of cytokine-induced memory-like (CIML) NK cells from RA patients and healthy volunteers. Data was presented as percent expression (%) ± SEM. ((a) healthy volunteers n = 15, RA n = 12 (b) healthy volunteers n = 15, RA n = 11 (c) healthy volunteers n = 15, RA n = 12 (d) healthy volunteers n = 14, RA n = 10). * means p < 0.05, ** means p < 0.01.
Figure 4
Figure 4
Correlation between (a) percentages of CD56+CD3− NK cells and DAS28 score, n = 32; (b) NKp46 expression on NK cells and DAS28 score, n = 21; (c) CD158e expression on NK cells and DAS28 score, n = 10; (d) Perforin production of NK cells and DAS28 score, n = 28.
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