Analysis of the CXCL9-11 mediating recruitment of CXCR3+CD4 T cells to HDV-infected livers

Background & Aims: In this study, we characterized the induction pattern of inflammatory chemokines in HDV-infected primary human hepatocytes (PHHs) and CXCR3-mediated chemotaxis of T cells in chronic hepatitis D (CHD).

Methods: We performed qPCR, RNA in situ hybridization (ISH) and FACS analysis in liver biopsies and blood samples from patients with chronic HBV infection (CHB) and CHD. Chemokine expression was investigated in cultured HBV/HDV-infected PHHs and in livers of HBV/HDV-infected humanized mice, in the presence or absence of adoptively transferred human T cells.

Results: HDV infection highlighted CXCL9-11 as the most strongly induced chemokines. Interferon lambda-1 (IFNL1) was also strongly induced by HDV and blocking of the IFNL receptor before HDV infection resulted in reduced CXCL9-11 induction in cultured PHHs. ISH analysis of HDV-infected livers from patients and chimeric mouse revealed that PHHs substantially contribute to chemokine expression in vivo. Moreover, the corresponding chemokine receptor CXCR3 was enhanced on CD4 T cells in the periphery of CHD patients. CXCR3-upregulation was unspecific and was not detected on HDAg- or HBsAg-specific CD4 T cells by AIM assay. Adoptive transfer of human T cells in humanized mice led to the recruitment of non-HBV/HDV-specific CD4+T cells only in the setting of HBV/HDV co-infection, but not in HBV-mono-infected mice.

Conclusions: HDV infection enhanced the expression of CXCL9-11 in hepatocytes, and such induction was augmented by IFNL1 production. The CXCL9-11 increase correlated with the accumulation of bulk CXCR3+T cells in HDV-infected liver. This pathway may contribute to the aggravated liver inflammation in CHD patients.

Publication History

Article published online:
20 January 2025