Complementary HLH Susceptibility Factors Converge on CD8 T-cell Hyperactivation [bulk RNA-seq]

To determine the effects of excess IL-18 and perforin deficiency on CD8 T cells toegther and separately under homeostatic conditions. Mice harboring both excess IL-18 and perforin deficiency (DS) have increased activated (CD44+) CD8 t cells as well as a special CD44low/- CD62L- (DN) population of CD8 T cells. DS mice have CD8 T cells that have specifically upregulated inhibitory receptors Lag3, Havcr2, and Tigit, and the transcription factors Tox and Prdm1. Mice harboring excess IL-18 and partial perforin deficiency (DS-HET) as well as mice with only excess IL-18 (Il18tg) also have these signatures but only in the DN CD8 T cell population. These data support that IL-18 as a potent, independent, and modifiable driver of life-threatening innate nd adaptive hyperinflammation, and support the rationale for an IL-18-driven subclass of hyperinflammation. Overall design: FACS sorted CD8 T lymphocytes from Prfko, Il18tg, PrfHET18tg, and Prfko18tg mice under homeostatic conditions