Murine hemophagocytic lymphohistiocytosis can occur in the absence of interferon-gamma.

Abstract

Abstract Hemophagocytic lymphohistiocytosis (HLH) is an ultimately fatal disease manifesting as a result of a dysregulated systemic hyperinflammatory response. Infection of perforin knockout (PKO) mice with an acute strain of lymphocytic choriomeningitis virus (LCMV) mimics the human disease. Based on this murine model, the current dogma suggests that disease is driven by excessive production of interferon gamma (IFNγ) by hyper-proliferative, LCMV specific CD8+ T cells. Evidence in humans has however suggested that HLH can develop in the absence of IFNγ signaling. To test this possibility we developed a double knock-out (DKO) mouse lacking both perforin and IFNγ, and show that DKO mice develop multiple HLH disease characteristics to a similar extent to the PKO mice, including weight loss, elevated sCD25, cytopenia, and hepatitis. DKO mice had equivalent numbers of LCMV specific CD8+ T cells in the spleen, and increased numbers of CD8+ T cells displaying a terminal effector phenotype (p<0.05). Interestingly, DKO mice had extensive neutrophilia in the blood, liver, and spleen compared to PKO mice, correlating with elevated serum IL-6 (p<0.01) and IL-1β (p<0.05). We hypothesized that DKO CD8+ T cells drove HLH through an aberrant, type-17 skewing. Indeed, following ex vivo re-stimulation, there was a significant population of IL-17a producing CD8+ T cells, corroborated by an increase in IL-17a and IL-17f transcript levels in purified DKO CD8+ T cells. Overall, these data suggest that perforin deficient HLH can occur independently of IFNγ, which is important to consider as IFNγ blocking therapies begin clinical trials. Additionally we have potentially unveiled an important regulatory mechanism for IFNγ in the control of CD8+ T cell fate decisions.