USP18 as a novel regulator of PD-1 and IFNAR1-mediated immune dysfunction (IRM11P.629)

Abstract

Abstract Immune dysfunction induced by cancer and chronic viral infection contributes to the pathology and progression of each of these diseases. Recent studies have identified a novel player associated with poorly functioning immune cells during chronic viral infection, the ubiquitin-specific protease Usp18. Usp18 is a negative regulator of innate anti-viral responses through direct inhibition of Type I IFN receptor signaling. However, the role of Usp18 in maintaining functional immunity is still unclear. To investigate the role of Usp18 in immunity, we have utilized Usp18-deficient mice and assessed immune function during infection with the Th1 pathogen Listeria monocytogenes (Lm). We find that Usp18 deficiency results in severe susceptibility to acute Lm infection and an inability to develop functional adaptive immunity to Lm. Severe susceptibility to Lm infection in the Usp18-/- mouse is associated with poor inflammatory cytokine responses and blunted splenic T cell function. The immune tolerant state in Usp18-/- mice is partially regulated by the PD-1 inhibitory receptor as blockade partially restores innate responses to Lm. However, blockade of IFNAR1 signaling resulted in significant reversal of this immunosuppressive state and a restoration of T cell function. This study identifies Usp18 and IFNAR1 signaling as critical mediators of immune dysfunction, a finding that may have broad implications in the treatment of cancer and chronic viral infection.