Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai, China.
Nat Immunol. 2016 Oct;17(10):1167-75. doi: 10.1038/ni.3535. Epub 2016 Aug 22.
CD8α(+) dendritic cells (DCs) are specialized at cross-presenting extracellular antigens on major histocompatibility complex (MHC) class I molecules to initiate cytotoxic T lymphocyte (CTL) responses; however, details of the mechanisms that regulate cross-presentation remain unknown. We found lower expression of the lectin family member Siglec-G in CD8α(+) DCs, and Siglec-G deficient (Siglecg(-/-)) mice generated more antigen-specific CTLs to inhibit intracellular bacterial infection and tumor growth. MHC class I-peptide complexes were more abundant on Siglecg(-/-) CD8α(+) DCs than on Siglecg(+/+) CD8α(+) DCs. Mechanistically, phagosome-expressed Siglec-G recruited the phosphatase SHP-1, which dephosphorylated the NADPH oxidase component p47(phox) and inhibited the activation of NOX2 on phagosomes. This resulted in excessive hydrolysis of exogenous antigens, which led to diminished formation of MHC class I-peptide complexes for cross-presentation. Therefore, Siglec-G inhibited DC cross-presentation by impairing such complex formation, and our results add insight into the regulation of cross-presentation in adaptive immunity.
CD8α(+)树突状细胞 (DCs) 擅长在外源性抗原与主要组织相容性复合体 (MHC) Ⅰ类分子结合，以启动细胞毒性 T 淋巴细胞 (CTL) 反应；然而，调节交叉呈递的机制细节仍不清楚。我们发现 CD8α(+) DCs 中凝集素家族成员 Siglec-G 的表达水平较低，Siglec-G 缺陷 (Siglecg(-/-)) 小鼠产生了更多的抗原特异性 CTL，以抑制细胞内细菌感染和肿瘤生长。Siglecg(-/-) CD8α(+) DCs 上 MHC Ⅰ类肽复合物的丰度高于 Siglecg(+/+) CD8α(+) DCs。从机制上讲，吞噬体表达的 Siglec-G 募集了磷酸酶 SHP-1，后者使 NADPH 氧化酶成分 p47(phox)去磷酸化，并抑制吞噬体上 NOX2 的激活。这导致外源性抗原的过度水解，从而减少 MHC Ⅰ类肽复合物的形成，以进行交叉呈递。因此，Siglec-G 通过损害这种复合物的形成来抑制 DC 的交叉呈递，我们的结果为适应性免疫中的交叉呈递调节提供了新的见解。
