Venzin and Beccaria et al. demonstrate that pre-activated CD4+ T cells actively license local hepatic APCs and restore antiviral CD8+ T cell function. HBV-specific CD4+ T cell receptor transgenic mice show that effector CD4+ T cells reprogram Kupffer cells (KCs), but not DCs, to rescue dysfunctional CD8+ T cells in a tolerogenic hepatic environment. CD4+ T cells activated KCs via CD40L-CD40 interactions prompting IL-12 and IL-27 production. IL-12 amplified the helper CD4+ T cells and IL-27 reinvigorated dysfunctional CD8+ T cells. Exogenous IL-27 reinstated HBV-specific CD8+ T cell effector function in T cells from chronically infected patients.
Contributed by Shishir Pant
ABSTRACT: Chronic hepatitis B virus (HBV) infection is marked by dysfunctional HBV-specific CD8+ T cells, and restoring their effector activity is a major therapeutic goal. Here, we generated HBV-specific CD4+ T cell receptor transgenic mice to show that CD4+ effector T cells can prevent and reverse the CD8⁺ T cell dysfunction induced by hepatocellular priming. This rescue enhances antiviral CD8+ T cell function and suppresses viral replication. CD4+ T cell help occurs directly within the liver, independent of secondary lymphoid organs, and requires local antigen recognition. Kupffer cells, rather than dendritic cells, are the critical antigen-presenting platform. CD4+ T cells license Kupffer cells via CD40-CD40L interactions, triggering interleukin (IL)-12 and IL-27 production. IL-12 expands the CD4+ T cell pool, while IL-27 is essential for CD8+ T cell rescue. Exogenous IL-27 similarly restores HBV-specific CD8+ T cell function in mice and in T cells isolated from chronically infected patients. These findings identify IL-27 as a tractable immunotherapeutic target in chronic HBV infection.
Author Info: (1) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (2)
Author Info: (1) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (2) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (3) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (4) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (5) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (6) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (7) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy. (8) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (9) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (10) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy. (11) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (12) Biopharmaceutical New Technologies (BioNTech), BioNTech Cell & Gene Therapies GmbH, Mainz, Germany. (13) Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany. (14) Biopharmaceutical New Technologies (BioNTech), BioNTech Cell & Gene Therapies GmbH, Mainz, Germany. (15) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (16) Emerging Infectious Disease Program, Duke-NUS Medical School, Singapore, Singapore. Department of Molecular Medicine, University of Pavia, Pavia, Italy. (17) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (18) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (19) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (20) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (21) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (22) Department of Hepatology, Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. (23) Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Ghent, Belgium. Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium. (24) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (25) Vita-Salute San Raffaele University, Milan, Italy. Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. (26) Vita-Salute San Raffaele University, Milan, Italy. Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. (27) Biopharmaceutical New Technologies (BioNTech), BioNTech Cell & Gene Therapies GmbH, Mainz, Germany. TRON, Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz gGmbH, Mainz, Germany. (28) Emerging Infectious Disease Program, Duke-NUS Medical School, Singapore, Singapore. (29) Emerging Infectious Disease Program, Duke-NUS Medical School, Singapore, Singapore. (30) TRON, Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz gGmbH, Mainz, Germany. (31) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. (32) Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. iannacone.matteo@hsr.it. Vita-Salute San Raffaele University, Milan, Italy. iannacone.matteo@hsr.it. Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy. iannacone.matteo@hsr.it.
