Yongyin Li1, Libo Tang1, Ling Guo1, Chengcong Chen1, Shuqin Gu1, Yang Zhou1, Guofu Ye1, Xiaoyi Li1, Weibin Wang1, Xinxin Liao2, Yu Wang3, Xiaohong Peng4, Guangze Liu5, Xiaoyong Zhang1, Jian Sun1, Jie Peng1, Jinlin Hou6. 1. State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China. 2. Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China. 3. Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China. 4. Department of Otolaryngology, Nanfang Hospital, Southern Medical University, Guangzhou, China. 5. Liver Disease Research Center, the 458th Hospital of the Chinese People's Liberation Army, Guangzhou, China. 6. State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address: jlhousmu@163.com.
Abstract
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.
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.
Authors: Ildefonso Sánchez-Cerrillo; Pedro Landete; Beatriz Aldave; Santiago Sánchez-Alonso; Ana Sánchez-Azofra; Ana Marcos-Jiménez; Elena Ávalos; Ana Alcaraz-Serna; Ignacio de Los Santos; Tamara Mateu-Albero; Laura Esparcia; Celia López-Sanz; Pedro Martínez-Fleta; Ligia Gabrie; Luciana Del Campo Guerola; Hortensia de la Fuente; María J Calzada; Isidoro González-Álvaro; Arantzazu Alfranca; Francisco Sánchez-Madrid; Cecilia Muñoz-Calleja; Joan B Soriano; Julio Ancochea; Enrique Martín-Gayo Journal: J Clin Invest Date: 2020-12-01 Impact factor: 14.808