Department of Medicine, The University of Hong Kong.
State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
J Clin Gastroenterol. 2022 Jan 1;56(1):e31-e37. doi: 10.1097/MCG.0000000000001461.
Regulatory T cells (Tregs) possess hepatitis B virus (HBV)-specific immunoregulatory effects in chronic HBV infection. The role of Tregs in spontaneous seroclearance of hepatitis B surface antigen (HBsAg) remains to be determined.
We recruited treatment-naive chronic HBV patients achieving spontaneous HBsAg seroclearance (experimental group) and matched HBsAg-positive controls. Peripheral blood mononuclear cells were isolated using the Ficoll-Paque density gradient centrifugation method. The frequency of Tregs and inhibitory phenotypes and immunoregulatory cytokines of Tregs were detected by flow cytometry.
Twenty-seven patients with HBsAg seroclearance (mean age: 52.40±6.00 y, 55.6% male) and 27 matched controls were recruited. Median HBsAg and HBV DNA levels in the control group were 2.80 (1.24 to 3.43) and 3.16 (1.68 to 3.85) log IU/mL, respectively. Mean frequencies of Tregs and expressions of FoxP3+ Tregs were comparable in both groups (both P>0.05). The mean expression of programmed death 1 (PD-1) and glucocorticoid-induced TNFR family-related gene (GITR) in total CD4+ T cells were significantly downregulated in the experimental group when compared with the control group (10.62% vs. 13.85%, P=0.003; 16.20% vs. 27.02%, P=0.002, respectively). When compared with the control group, PD-1+CD4+ Tregs expression in the experimental group was significantly downregulated (13.85% vs. 10.62%, P=0.003). A similar phenomenon was noted for GITR+CD8+ Tregs (20.16% vs. 14.08%, P=0.049). Intracellular cytokine productions showed no significant differences (all P>0.05).
The reduced expression of PD-1 and GITR might attenuate the immunosuppressive capability of Tregs. Decreased expression on CD4+ T cells might represent an enhanced antiviral function, playing a role in initiating the "functional cure" of chronic HBV infection.
调节性 T 细胞（Tregs）在慢性乙型肝炎病毒（HBV）感染中具有 HBV 特异性免疫调节作用。Tregs 在乙型肝炎表面抗原（HBsAg）自发清除中的作用仍有待确定。
我们招募了未经治疗的慢性 HBV 患者，这些患者实现了 HBsAg 血清学清除（实验组），并匹配了 HBsAg 阳性对照。使用 Ficoll-Paque 密度梯度离心法分离外周血单核细胞。通过流式细胞术检测 Tregs 的频率以及 Tregs 的抑制表型和免疫调节细胞因子。
招募了 27 例 HBsAg 血清学清除患者（平均年龄：52.40±6.00 岁，55.6%为男性）和 27 例匹配对照。对照组的 HBsAg 和 HBV DNA 中位数水平分别为 2.80（1.24 至 3.43）和 3.16（1.68 至 3.85）log IU/mL。两组的 Tregs 频率和 FoxP3+Tregs 的表达均无差异（均 P＞0.05）。与对照组相比，实验组总 CD4+T 细胞中程序性死亡 1（PD-1）和糖皮质激素诱导的 TNFR 家族相关基因（GITR）的平均表达显著下调（10.62%比 13.85%，P=0.003；16.20%比 27.02%，P=0.002，分别）。与对照组相比，实验组 PD-1+CD4+Tregs 的表达显著下调（13.85%比 10.62%，P=0.003）。GITR+CD8+Tregs 也出现类似现象（20.16%比 14.08%，P=0.049）。细胞内细胞因子产生无显著差异（均 P＞0.05）。
PD-1 和 GITR 的表达减少可能会削弱 Tregs 的免疫抑制能力。CD4+T 细胞上表达的减少可能代表抗病毒功能增强，在启动慢性 HBV 感染的“功能性治愈”中发挥作用。
