Cytotoxic Function and Cytokine Production of Natural Killer Cells and Natural Killer T-Like Cells in Systemic Lupus Erythematosis Regulation with Interleukin-15.

Syh-Jae Lin,Ji-Yih Chen,Hsiu-Shan Hsiao,Wen-I Lee,Ming-Ling Kuo,Pei-Tzu Lee,Jing-Long Huang

doi:10.1155/2019/4236562

Abstract

Natural killer cells and NKT-like cells are the first line immune defense against tumor and virus infection. Deficient NK and NKT-like cell effector function may contribute to increased susceptibility to infection in SLE patients. We sought to examine the perforin and granzyme B expression, interferon-gamma (IFN-γ), and tumor-necrosis factor-alpha (TNF-α) production and CD107a degranulation of NK and NKT-like cells from SLE patients and their regulation by IL-15. We established that (1) perforin expression on SLE NK cells was decreased but unrelated to disease activity; (2) the MFI of granzyme B was increased in NK cells from SLE patients with active disease, associated with increased percentages of granzyme B+ CD56bright NK cells; (3) NK cells from active SLE patients, both CD56dim and CD56bright NK subsets, produced higher IFN-γ compared to controls; (4) CD56dim, but not CD56bright NK cells from active SLE patients, produced lower TNF-α, compared to inactive SLE patients and controls; (5) CD107a degranulation of SLE NK cells was comparable to controls; (6) IL-15 enhanced perforin/granzyme B expression, IFN-γ/TNF-α production, and CD107a degranulation of NK cells from SLE patients; and (7) similar observations were found for CD56+CD3+ NKT-like cells. Taken together, we demonstrated the differential expression of the heightened granzyme B and decreased TNF-α in NK and NKT-like cells in SLE patients. Higher granzyme B expression of NK and NKT-like cells in active SLE patients, further enhanced by circulating IL-15, may contribute to the maintenance of inflammation in SLE.

Highlights

Natural killer (NK) cells are a distinct lineage of CD3, CD16+, and/or CD56+ lymphoid cells capable of killing tumor target without prior sensitization and produce various cytokines and chemokines which amplify an inflammatory response [1, 2]
We established that (1) perforin expression on Systemic lupus erythematosus (SLE) NK cells was decreased but unrelated to disease activity; (2) the mean fluorescence intensity (MFI) of granzyme B was increased in NK cells from SLE patients with active disease, associated with increased percentages of granzyme B+ CD56bright NK cells; (3) NK cells from active SLE patients, both CD56dim and CD56bright NK subsets, produced higher IFN-γ compared to controls; (4) CD56dim, but not CD56bright NK cells from active SLE patients, produced lower TNF-α, compared to inactive SLE patients and controls; (5) CD107a degranulation of SLE NK cells was comparable to controls; (6) IL-15 enhanced perforin/granzyme B expression, IFN-γ/TNF-α production, and CD107a degranulation of NK cells from SLE patients; and (7) similar observations were found for CD56+CD3+ NKT-like cells
Perforin is a 70 kDa glycoprotein responsible for pore formation in the cell membrane of target cells induced by NK cells [19]

Summary

Introduction

Natural killer (NK) cells are a distinct lineage of CD3-, CD16+, and/or CD56+ lymphoid cells capable of killing tumor target without prior sensitization and produce various cytokines and chemokines which amplify an inflammatory response [1, 2]. The NK cells consist of two subsets: CD56dim CD16+ NK subset which is more cytotoxic and CD56bright CD16- subset which produces abundant cytokines and plays an important immunoregulatory role [3, 4]. CD3+CD56+ NKT-like cells have been demonstrated to play an important role in antitumor and antivirus immune response [7, 8]. Previous works including ours have examined the various functional and numeric deficiencies of NK cells [4, 12, 13] and NKT-like cells [14, 15] from SLE patients. We investigated the cytotoxic function (perforin/granzyme B expression and CD107a degranulation) and cytokine production (IFN-γ and TNF-α) of NK (including NKdim and NKbright subsets) and NKT-like cells from SLE patients in various disease statuses. We sought to determine whether IL-15, an NK-enhancing cytokine, would differentially affect their expression in SLE and healthy controls

Methods

Result

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Discussion