Szereday Laszlo, Meggyes Matyas, Halasz Melinda, Szekeres-Bartho Julia, Par Alajos, Par Gabriella
Laszlo Szereday, Matyas Meggyes, Melinda Halasz, Julia Szekeres-Bartho, Department of Medical Microbiology and Immunology, University of Pecs, Clinical Centre, 7624 Pecs, Hungary.
World J Gastroenterol. 2016 May 28;22(20):4848-59. doi: 10.3748/wjg.v22.i20.4848.
To investigate killer inhibitory and activating receptor expression by natural killer (NK), natural killer T-like (NKT-like) and CD8+ T lymphocytes in patients with chronic hepatitis C virus (HCV) infection with elevated and with persistently normal alanine aminotransferase (PNALT).
The percentage of peripheral blood Treg cells, KIR2DL3, ILT-2, KIR3DL1, CD160, NKG2D, NKG2C expressing NK, T and NKT-like cells, cytokine production and NK cytotoxicity were determined by flow cytometry. Twenty-one patients with chronic HCV infection with elevated alanine aminotransferase, 11 HCV carriers with persistently normal alanine aminotransferase and 15 healthy volunteers were enrolled.
No significant differences were observed in the percentage of total T, NK or NKT-like cells between study groups. Comparing the activating and inhibitory receptor expression by NK cells obtained from HCV carriers with PNALT and chronic HCV hepatitis patients with elevated alanine aminotransferase, NKG2D activating receptor expression was the only receptor showing a significant difference. NKG2D expression of NK cells was significantly lower in patients with elevated alanine aminotransferase. The expression of CD160, NKG2D and NKG2C activating receptor by CD8+ T cells were significantly lower in patients with chronic HCV hepatitis than in healthy controls and in HCV carriers with PNALT. Plasma TGF-β1 levels inversely correlated with NKG2D expression by NK cells. In vitroTGF-β1 treatment inhibited NK cells cytotoxic activity and downregulated NKG2D expression. CD8+ T cells from HCV carriers with PNALT showed significantly elevated expression of CD160, NKG2D and NKG2C activating receptors compared to chronic HCV patients with elevated alanine aminotransferase. Enhanced expression of inhibitory KIR2DL3 receptor, and decreased ILT-2 expression on NK cells were also found in chronic hepatitis C patients compared to healthy controls.
Our study demonstrated a complex dysregulation of activating and inhibitory receptor expression, such as decreased NKG2D and CD160 activating receptor expression and increased KIR2DL3 inhibitory receptor expression by NK and cytotoxic T cells and may provide further mechanism contributing to defective cellular immune functions in chronic hepatitis C. Increased NKG2D receptor expression in HCV patients with persistently normal ALT suggests an important pathway for sustaining NK and CD8 T cell function and a protective role against disease progression.
研究慢性丙型肝炎病毒（HCV）感染且丙氨酸转氨酶（ALT）升高及持续正常（PNALT）患者中自然杀伤（NK）细胞、自然杀伤T样（NKT样）细胞和CD8⁺T淋巴细胞的杀伤抑制性和激活性受体表达情况。
通过流式细胞术测定外周血调节性T细胞（Treg）、KIR2DL3、ILT - 2、KIR3DL1、CD160、NKG2D、NKG2C表达的NK、T和NKT样细胞的百分比、细胞因子产生及NK细胞毒性。纳入21例丙氨酸转氨酶升高的慢性HCV感染患者、11例丙氨酸转氨酶持续正常的HCV携带者及15名健康志愿者。
研究组间总T细胞、NK细胞或NKT样细胞百分比无显著差异。比较从PNALT的HCV携带者及丙氨酸转氨酶升高的慢性HCV肝炎患者获得的NK细胞的激活性和抑制性受体表达，NKG2D激活性受体表达是唯一显示出显著差异的受体。丙氨酸转氨酶升高患者的NK细胞NKG2D表达显著降低。慢性HCV肝炎患者CD8⁺T细胞的CD160、NKG2D和NKG2C激活性受体表达显著低于健康对照及PNALT的HCV携带者。血浆转化生长因子 - β1（TGF - β1）水平与NK细胞的NKG2D表达呈负相关。体外TGF - β1处理抑制NK细胞的细胞毒性活性并下调NKG2D表达。与丙氨酸转氨酶升高的慢性HCV患者相比，PNALT的HCV携带者的CD8⁺T细胞显示出CD160、NKG2D和NKG2C激活性受体表达显著升高。与健康对照相比，慢性丙型肝炎患者NK细胞上抑制性KIR2DL3受体表达增强，ILT - 2表达降低。
我们的研究表明激活性和抑制性受体表达存在复杂的失调，如NK细胞和细胞毒性T细胞的NKG2D和CD160激活性受体表达降低以及KIR2DL3抑制性受体表达增加，这可能为慢性丙型肝炎细胞免疫功能缺陷提供进一步的机制。ALT持续正常的HCV患者中NKG2D受体表达增加提示维持NK和CD8 T细胞功能的重要途径以及对疾病进展的保护作用。
