CXCL13-mediated recruitment of intrahepatic CXCR5+CD8+T cells favors viral control in chronic HBV infection

Abstract Background & Aims Although CD8+T cell exhaustion hampers viral control during chronic hepatitis B virus (HBV) infection, the pool of CD8+T cells is phenotypically and functionally heterogeneous. Therefore, a specific subpopulation of CD8+T cells should be further investigated. This study aims to dissect a subset of CD8+T cells expressing C-X-C motif chemokine receptor 5 (CXCR5) in chronic HBV infection. Methods The frequency of CXCR5+CD8+T cells and the levels of C-X-C motif chemokine ligand 13 (CXCL13), a chemokine of CXCR5, were measured in patients with chronic HBV infection. C57BL/6, interleukin (IL)-21 receptor- or B cell-deficient mice were hydrodynamically injected with pAAV-HBV1.2 plasmids. Phenotype and functions of peripheral and intrahepatic CXCR5+ and CXCR5−CD8+T cells were assessed. Results CXCR5+CD8+T cells were partially exhausted but possessed a stronger antiviral ability than the CXCR5− subset in patients with chronic HBV infection; moreover, CXCR5+CD8+T cells were associated with a favorable treatment response in chronic hepatitis B (CHB) patients. High levels of CXCL13 from CHB patients facilitated the recruitment of intrahepatic CXCR5+CD8+T cells, and this subpopulation produced high levels of HBV-specific interferon (IFN)-γ and IL-21. Notably, programmed death 1 (PD1) blockade and exogenous IL-21 enhanced the production of IFN-γ. More strikingly, mice injected with CXCR5+CD8+T cells showed remarkably decreased expression of HBsAg. Additionally, an impaired production of HBV-specific IFN-γ from intrahepatic CXCR5+CD8+T cells was observed in IL-21 receptor- or B cell-deficient mice. Conclusion CXCL13 promotes the recruitment of CXCR5+CD8+T cells to the liver, and this subpopulation benefits viral control in chronic HBV infection. The identification of this unique subpopulation may contribute to a better understanding of CD8+T cell functions and provide a potential immunotherapeutic target in chronic HBV infection. Lay summary CXCR5+CD8+T cells are partially exhausted while possess a more potent antiviral activity through producing high levels of HBV-specific IFN-γ and IL-21 in chronic HBV infection. Increased expression of intrahepatic CXCL13 facilitates the recruitment of CXCR5+CD8+T cells to the liver and establishes an effective immune control of HBV infection.