Chronic liver infections: New in-situ insights into the dynamic regulation of exhausted CD8+ T cell subsets

Abstract

Chronic hepatotropic viral infections represent a major challenge in current medicine. Chronic infections are a consequence of dysfunctional CD8+ T cell responses which impair effective viral clearance. Dysfunction in CD8+ T cells, as a result of T cell exhaustion, lift the break on viral replication, thereby promoting the development of liver diseases. Currently, immunomodulatory strategies are being explored as an attractive option to reinvigorate exhausted T cells in chronic infection as well as in cancer. However, the dynamic regulation of exhausted T cells as well as the mechanisms enforcing reinvigoration of exhausted T cells in the liver are not clearly defined. In this study, an OvaXCre transgenic mouse model characterized by antigen expression specifically in the liver was used to elucidate the dynamic differentiation and reinvigoration of exhausted T cells in the liver. The expression of antigen in a fraction of hepatocytes mimics persisting antigen situation in chronic liver infections. In this regard, it was observed that host conditioning with CpG oligodeoxynucleotides (CpG ODN), which modulates the liver environment, translates into eradication of chronic Ova-antigen from the liver by the action of cytotoxic T cells, probably as a result of exhausted T cell reinvigoration. Interestingly, antigen clearance was accompanied with an extreme loss of antigen specific T cells and T cell stemness. In depth characterization of exhausted T cells in liver revealed two distinct T cell subsets, identified by presence or absence of the chemokine receptor CXCR5. CXCR5+ and CXCR5- T cells exhibit profound differences in cytotoxic, effector and memory functions, with all these functional capacities skewed towards CXCR5+ T cells in the liver. The CXCR5+ T cells are follicular-like and liver resident cells by virtue of upregulation of the transcription factors Bcl6 and LFA-1. Robust and efficient mitochondria activities were manifested in CXCR5+ T cells, which was in contrast to CXCR5- T cells. Importantly, CXCR5+ T cells demonstrated a significant nutrient acquisition advantage and show enhanced recall responses and self-maintenance in vivo. In sum, these data show that CpG ODN immunomodulation reinvigorates exhausted T cells. While heterogeneity exists in the intrahepatic pool of exhausted T cells, the CXCR5+ T cell subset plays a major role in eliminating chronic antigen expression in liver. Therefore, this subset may be of interest for the development of novel immune based therapeutic strategies against chronic liver infections.