Dysregulated Generation of Follicular Helper T Cells in the Spleen Triggers Fatal Autoimmune Hepatitis in Mice
2011
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.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
30
References
57
Citations
NaN
KQI