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

• Published in: Molecular immunology Vol. 135; pp. 217 - 225
• Main Authors: Sasawatari, Shigemi, Karyu, Hitomi, Nguyen Tien, Dat, Furuyama-Tanaka, Kaori, Toyama-Sorimachi, Noriko
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-07-2021
• Subjects: Cell surface molecule; MHC class I; NK receptor; Plasmacytoid dendritic cells; Pyroptosis; Rodent; Toll-like receptor; NK receptor; Cell surface molecule; Plasmacytoid dendritic cells; Pyroptosis; MHC class I; Rodent; Toll-like receptor
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2021.03.023

•CpG-ODN stimulation induced cell death in Ly49Q-deficient BMDCs in both in vivo and in vitro.•Ly49Q-deficient BMDCs secreted increased amounts of IL-1β upon CpG-ODN stimulation.•Ly49Q protects pDCs from CpG-induced cell death in vivo.•Ly49Q’s interaction with MHC class I facilitates pDC survival through the ITIM-mediated regulation of lysosome integrity.
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.