Background & aims: Although CD8⁺T cell exhaustion hampers viral control during chronic 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 patients with chronic hepatitis B (CHB). High levels of CXCL13 from patients with CHB 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, PD1 (programmed death 1) 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 improves 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: Exhaustion of CD8⁺ T cells is an important factor in the development of chronic hepatitis B virus (HBV) infection. CD8⁺ T cells expressing the receptor CXCR5 are partially exhausted, but have potent antiviral activity, as they produce high levels of HBV-specific cytokines in chronic HBV infection. Increased expression of CXCL13 within the liver facilitates the recruitment of CXCR5⁺CD8⁺T cells and establishes effective immune control of HBV infection.