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

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.