title: The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells.
abstract: Optimal immune activation of naïve CD8 T cells requires signal 1 mediated by the T cell receptor, signal 2 mediated by co-stimulation and signal 3 provided by pro-inflammatory cytokines. However, the potential for signal 3 cytokines to rescue anti-viral responses in functionally exhausted T cells has not been defined. We investigated the effect of using third signal cytokines IL-12 or IFN-α to rescue the exhausted CD8 T cell response characteristic of patients persistently infected with hepatitis B virus (HBV). We found that IL-12, but not IFN-α, potently augmented the capacity of HBV-specific CD8 T cells to produce effector cytokines upon stimulation by cognate antigen. Functional recovery mediated by IL-12 was accompanied by down-modulation of the hallmark inhibitory receptor PD-1 and an increase in the transcription factor T-bet. PD-1 down-regulation was observed in HBV but not CMV-specific T cells, in line with our finding that the highly functional CMV response was not further enhanced by IL-12. IL-12 enhanced a number of characteristics of HBV-specific T cells important for viral control: cytotoxicity, polyfunctionality and multispecificity. Furthermore, IL-12 significantly decreased the pro-apoptotic molecule Bim, which is capable of mediating premature attrition of HBV-specific CD8 T cells. Combining IL-12 with blockade of the PD-1 pathway further increased CD8 functionality in the majority of patients. These data provide new insights into the distinct signalling requirements of exhausted T cells and the potential to recover responses optimised to control persistent viral infections.
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Schurich
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Pallett
authors.forename: Marcin
authors.initials: M
authors.lastname: Lubowiecki
authors.forename: Harsimran D
authors.initials: HD
authors.lastname: Singh
authors.forename: Upkar S
authors.initials: US
authors.lastname: Gill
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Kennedy
authors.forename: Eleni
authors.initials: E
authors.lastname: Nastouli
authors.forename: Sudeep
authors.initials: S
authors.lastname: Tanwar
authors.forename: William
authors.initials: W
authors.lastname: Rosenberg
authors.forename: Mala K
authors.initials: MK
authors.lastname: Maini
mesh_terms: D000998:Antiviral Agents / Q000276:immunology / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015536:Down-Regulation; D015967:Gene Expression Regulation, Viral; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013045:Species Specificity
chemical_list: D000998:Antiviral Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D016207:Cytokines; D016898:Interferon-alpha; D008565:Membrane Proteins; D061026:Programmed Cell Death 1 Receptor; D011518:Proto-Oncogene Proteins; D018664:Interleukin-12