The mutated gene, called Unc13d, was identified in a screen for chemically induced mutations that make mice susceptible to murine cytomegalovirus (MCMV). Mutations in the Unc13d orthologue MUNC13-4 are associated with a severe human disease characterized by the uncontrolled proliferation of CD8⁺ T cells. These cells produce cytokines but fail to release cytotoxic granules, as MUNC13-4 is required for the fusion of granules with the plasma membrane.

The Unc13d-deficient mice, which the team called Jinx, also had the same degranulation defect in their CD8⁺ T cells. They did not, however, develop the fatal lymphoproliferative disease seen in humans unless they were also infected with lymphochoriomeningitis virus—a pathogen that elicits robust T cell expansion. MCMV infection did not cause the disease, probably because the mice succumbed too quickly to the virus.

The pathogenesis of the human disease has so far been unclear. This study now suggests that the disease is triggered in MUNC13-4–deficient humans after infection with a pathogen stimulates a strong but ultimately ineffective CD8⁺ T cell expansion. The T cells might prompt cytokine-driven expansion of virus-infected APCs without killing them. The APCs, in turn, might drive further expansion of T cells, with each cell type stimulating the other in a vicious cycle.

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Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis

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