Department of Molecular Immunology and Inflammation, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
Department of Molecular Immunology and Inflammation, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
Mol Immunol. 2021 Jul;135:217-225. doi: 10.1016/j.molimm.2021.03.023. Epub 2021 Apr 28.
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.
Ly49Q 是一种带有 ITIM 的 MHC Ⅰ类受体，在浆细胞样树突状细胞（pDC）中高度表达。尽管其机制尚未完全阐明，但 Ly49Q 对于 TLR9 介导的 pDC 中 IFN-I 的产生是必需的。我们在此证明，Ly49Q 可保护 pDC 免受 CpG 寡脱氧核苷酸（CpG）诱导的细胞焦亡。在 Ly49Q 缺陷型（Klra17）小鼠脾脏中，CpG 处理后 ssDNA 阳性 pDC 的数量显著增加，强烈表明 Klra17 pDC 易受 CpG 诱导的细胞死亡。在 Klra17 骨髓来源的树突状细胞（BMDC）中，CpG 诱导的细胞死亡伴随着溶酶体囊泡中组织蛋白酶 B 向细胞质的渗漏增加。同时，CpG 处理的 Klra17 BMDC 中 IL-1β 的分泌增加，强烈表明这些细胞中的 CpG 诱导的细胞死亡本质上是细胞焦亡。与这些观察结果一致，在 CpG 刺激的 Klra17 BMDC 中抑制组织蛋白酶 B 或半胱天冬酶 1 可逆转细胞死亡的增加。在表达无 ITIM 的 Ly49Q（Ly49Q-YF Tg）的转基因小鼠来源的 BMDC 中也观察到细胞焦亡和 IL-1β 分泌。CpG 还增加了 B2m BMDC 中的 IL-1β 产生和细胞死亡。这些结果表明，Ly49Q 和 MHC Ⅰ类通过影响溶酶体状态在保护 DC 细胞的细胞焦亡样死亡中发挥重要作用。
