The inhibitory NK receptor Ly49Q protects plasmacytoid dendritic cells from pyroptotic cell death

Ly49Q is an ITIM-bearing MHC class I receptor that is highly expressed in plasmacytoid dendritic cells (pDCs). Ly49Q is required for the TLR9-mediated IFN-I production in pDCs, although the mechanism is not fully understood. We here demonstrate that Ly49Q protects pDCs from pyroptotic cell death induced by CpG oligodeoxynucleotides (CpG). In the Ly49Q-deficient (Klra17^-/-) mouse spleen, the number of ssDNA-positive pDCs increased significantly after CpG treatment, strongly suggesting that Klra17^-/- pDCs were susceptible to CpG-induced cell death. In Klra17^-/- bone-marrow-derived dendritic cells (BMDCs), CpG-induced cell death was accompanied by increased cathepsin B leakage from the vesicular compartments into the cytoplasm. Concurrently, IL-1β secretion increased in the CpG-treated Klra17^-/- BMDCs, strongly suggesting that the CpG-induced cell death in these cells is pyroptotic in nature. Consistent with these observations, inhibiting cathepsin B or caspase 1 in CpG-stimulated Klra17^-/- BMDCs reversed the increase in cell death. Pyroptotic cell death and IL-1β secretion were also observed in BMDCs derived from transgenic mice expressing an ITIM-less Ly49Q (Ly49Q-YF Tg). CpG also increased the IL-1β production and cell death in B2m^-/- BMDCs. These results suggest that Ly49Q and MHC class I play important roles for protecting pyroptosis-like cell death of DCs by influencing lysosome state.