The NLRP3 Inflammasome Impairs CD8+ T Cell Responses in Murine Viral Hepatitis.

DUHALDE VEGA M,; JELDRES, MATHIAS; CUTURI, MARÍA CRISTINA; HILL, MARCELO

San Francisco

Congreso; FOCIS 2018; 2018

FOCIS

NLRP3, caspase 1 and IL-1 are known to be required to mount adaptive CD8+ T cell responses against IAV. However, inviral hepatitis, IL-1beta production through the NLRP3 inflammasome has been associated to liver inflammation andincreased viral load. We have described the intracellular cation channel Tmem176b as a novel inhibitor of the NLP3inflammasome. Interestingly, Tmem176b has been associated to HCV clearance in humans. We therefore speculatedthat Tmem176b might promote viral clearance by inhibiting inflammasome activation. We infected in vitro WT andTmem176b-/- DCs with murine hepatitis virus-A59 (MHV-A59) and studied inflammasome activation. MHV-A59 inducedcaspase 1 activation and IL-1beta secretion in an NLRP3-dependent manner. Tmem176b-/- DCs showed increasedinflammasome activation as compared to WT DCs. In vivo, 7/7 Tmem176b-/- mice died within 5.5 days post-infectionwhereas 4/6 WT mice survived to infection. Liver viral load was higher in Tmem176b-/- mice. IL-1beta blockadesignificantly protected Tmem176b-/- mice in a CD8-dependent manner. In agreement with these observations, MHVA59-infectedTmem176b-/- animals had fewer total and MHV-A59-specific CD8+ T cells and decreased in vivo CD8-dependent cytotoxicity against MHV-A59 antigens. In compliment to these studies MHV-A59 infection of caspase 1/11-/-mice showed improved survival, diminished viral load and augmented total and MHV-A5-specific CD8+ T cells as well asincreased in vivo cytotoxicity against vial antigens. Inflammasome activation led to increased PD-1 expression in totaland virus-specific CD8+ T cells. Injection of anti-PD1 antibodies significantly improved the survival of MHV-A59-infectedTmem176b-/- mice. Thus, the NLRP3 inflammasome impairs anti-viral CD8 responses through PD-1