Dysregulated Generation of Follicular Helper T Cells in the Spleen Triggers Fatal Autoimmune Hepatitis in Mice
Dysregulated Generation of Follicular Helper T Cells in the Spleen Triggers Fatal Autoimmune Hepatitis in Mice
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DOI：
10.1053/j.gastro.2011.01.002
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发表时间：
2011-04-01
期刊：
影响因子：
29.4
通讯作者：
Watanabe, Norihiko
中科院分区：
文献类型：
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作者：
Aoki, Nobuhiro;Kido, Masahiro;Watanabe, Norihiko
背景与目的：为了阐明自身免疫性肝炎（AIH）发生的机制，我们最近通过诱导Foxp 3（+）调节性T细胞和程序性细胞死亡1（PD-1）介导的信号转导同时丢失，建立了自发性AIH小鼠模型。这些小鼠的致命性AIH的特征是严重的T细胞浸润和大量产生的抗核抗体（Abs）。本研究旨在确定AIH的诱导位点、负责的T细胞亚群和诱导AIH的关键分子。方法：采用PD-1基因缺陷（PD-1（-/-））小鼠行新生胸腺切除术（NTx），建立AIH小鼠模型。然后，我们进行新生儿脾切除术或在体内给予抗体的细胞因子，趋化因子，或细胞表面分子。研究结果：在NTx-PD-1（-/-）小鼠中，新生儿脾切除术或体内CD 4（+）T细胞耗竭抑制了肝脏中的CD 4（+）和CD 8（+）T细胞浸润。在AIH的诱导期，脾脏CD 4（+）T细胞定位于具有巨大生发中心的B细胞滤泡中，并表现出Bcl 6（+）诱导型共刺激分子（ICOS）（+）白细胞介素（IL）-21（+）IL-21受体（IL-21 R）（+）滤泡辅助性T细胞（T-FH）表型。阻断ICOS或IL-21的Ab抑制T-FH细胞的产生和AIH的诱导。此外，由T-FH细胞产生的IL-21驱动CD 8（+）T细胞活化。脾脏T-FH细胞和CD 8（+）T细胞表达CCR 6，肝脏中CCL 20表达升高。给予抗CCL 20抑制了这些T细胞向肝脏的迁移和AIH的诱导。结论：脾脏中失调的T-FH细胞是诱导致死性AIH的原因，并且脾脏T细胞的CCR 6-CCL 20轴依赖性迁移对于在NTx-PD-1（-/-）小鼠中诱导AIH至关重要。
BACKGROUND & AIMS: To clarify mechanisms involved in the development of autoimmune hepatitis (AIH), we recently developed a mouse model of spontaneous AIH by inducing a concurrent loss of Foxp3(+) regulatory T cells and programmed cell death 1 (PD-1) mediated signaling. Fatal AIH in these mice was characterized by severe T-cell infiltration and huge production of antinuclear antibodies (Abs). This study aims to identify induction sites, responsible T-cell subsets, and key molecules for induction of AIH. METHODS: To develop the mouse model of AIH, neonatal thymectomy (NTx) was performed on PD-1-deficient (PD-1(-/-)) mice. We then conducted neonatal splenectomy or in vivo administration of Abs to cytokines, chemokines, or cell-surface molecules. RESULTS: In NTx-PD-1(-/-) mice, either neonatal splenectomy or in vivo CD4(+) T-cell depletion suppressed CD4(+) and CD8(+) T-cell infiltration in the liver. In the induction phase of AIH, splenic CD4(+) T cells were localized in B-cell follicles with huge germinal centers and showed the Bcl6(+) inducible costimulator (ICOS)(+) interleukin (IL)-21(+) IL-21 receptor (IL-21R)(+) follicular helper T (T-FH) cell phenotype. Blocking Abs to ICOS or IL-21 suppressed T-FH-cell generation and induction of AIH. In addition, IL-21 produced by T-FH cells drove CD8(+) T-cell activation. Splenic T-FH cells and CD8(+) T cells expressed CCR6, and CCL20 expression was elevated in the liver. Administration of anti-CCL20 suppressed migration of these T cells to the liver and induction of AIH. CONCLUSIONS: Dysregulated T-FH cells in the spleen are responsible for the induction of fatal AIH, and CCR6-CCL20 axis-dependent migration of splenic T cells is crucial to induce AIH in NTx-PD-1(-/-) mice.