Toll-Like Receptor 8 Agonist and Bacteria Trigger Potent Activation of Innate Immune Cells in Human Liver

Abstract

The ability of innate immune cells to sense and respond to impending danger varies by anatomical location. The liver is considered tolerogenic but is still capable of mounting a successful immune response to clear various infections. To understand whether hepatic immune cells tune their response to different infectious challenges, we probed mononuclear cells purified from human healthy and diseased livers with distinct pathogen-associated molecules. We discovered that only the TLR8 agonist ssRNA40 selectively activated liver-resident innate immune cells to produce substantial quantities of IFN-γ. We identified CD161Bright mucosal-associated invariant T (MAIT) and CD56Bright NK cells as the responding liver-resident innate immune cells. Their activation was not directly induced by the TLR8 agonist but was dependent on IL-12 and IL-18 production by ssRNA40-activated intrahepatic monocytes. Importantly, the ssRNA40-induced cytokine-dependent activation of MAIT cells mirrored responses induced by bacteria, i.e., generating a selective production of high levels of IFN-γ, without the concomitant production of TNF-α or IL-17A. The intrahepatic IFN-γ production could be detected not only in healthy livers, but also in HBV- or HCV-infected livers. In conclusion, the human liver harbors a network of immune cells able to modulate their immunological responses to different pathogen-associated molecules. Their ability to generate a strong production of IFN-γ upon stimulation with TLR8 agonist opens new therapeutic opportunities for the treatment of diverse liver pathologies.

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…MAIT cells are only a small fraction of the CD161++ CD8+ T‐cell population in cord blood,83 but slowly expand with age, making up more than 90% of the CD161++ CD8+ T‐cell population in adults 11, 14. Both MAIT and non‐MAIT CD161++ CD8+ T‐cells share functional features, most notably the ability to respond to innate cytokines in the absence of TCR stimulation, due to their high expression of cytokine receptors such as IL‐18R and IL‐12R 9, 84. This function is likely driven by the shared expression by MAIT and non‐MAIT CD161++ CD8+ T‐cells of the master transcription factor promyelocytic leukaemia zinc finger protein (PLZF) 14, 85…”

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

“…These results demonstrated the therapeutic implications of TLR8 agonists for the treatment of chronic liver infections. 80 Therefore, TLR3, 7 and 8 agonists are promising drug candidates for the treatment of chronic HBV infection if their toxicity can be reduced to a tolerated range.…”

Dissecting the dendritic cell controversy in chronic hepatitis B virus infection

“…We and others have characterized the cell populations flushed from the sinusoids of the healthy liver and showed significant variation in cellular content and cytokine profiles compared with PBMCs. [50][51][52] However, almost no information is available to compare the differences in these populations between HBV patients and healthy donors. Analyses of HBV-infected livers are often restricted to biopsy-sized samples or are explants due to advanced disease; as such, the processes required to extract cells are quite harsh, possibly interfering with or inhibiting downstream analysis.…”