Human C-type lectin member 18A (CLEC18A) is ubiquitously expressed in human, and highest expression levels are found in human myeloid cells and liver. In contrast, mouse CLEC18A (mCLEC18A) is only expressed in brain, kidney and heart. However, the biological functions of CLEC18A are still unclear. We have shown that a single amino acid change (S₃₃₉ →R₃₃₉) in CTLD domain has profound effect in their binding to polysaccharides and house dust mite allergens. In this study, we further demonstrate that CLEC18A and its mutant CLEC18A(S339R) associate with TLR3 in endosome and bind poly (I:C) specifically. Compared to TLR3 alone, binding affinity to poly (I:C) is further increased in TLR3-CLEC18A and TLR3-CLEC18A(S339R) complexes. Moreover, CLEC18A and CLEC18A(S339R) enhance the production of type I and type III interferons (IFNs), but not proinflammatory cytokines, in response to poly (I:C) or H5N1 influenza A virus (IAV) infection. Compared to wild type (WT) mice, ROSA-CLEC18A and ROSA-CLEC18A(S339R) mice generate higher amounts of interferons and are more resistant to H5N1 IAV infection. Thus, CLEC18A is a TLR3 co-receptor, and may contribute to the differential immune responses to poly (I:C) and IAV infection between human and mouse.

人 C 型凝集素成员 18A (CLEC18A) 在人体中普遍表达，在人骨髓细胞和肝脏中表达水平最高。相比之下，小鼠 CLEC18A (mCLEC18A) 仅在大脑、肾脏和心脏中表达。然而，CLEC18A的生物学功能仍不清楚。我们已经证明，CTLD 结构域中的单个氨基酸变化 (S ₃₃₉ →R ₃₃₉ ) 对它们与多糖和屋尘螨过敏原的结合具有深远的影响。在本研究中，我们进一步证明CLEC18A及其突变体CLEC18A(S339R)与内体中的TLR3相关并特异性结合聚(I:C)。与单独的 TLR3 相比，TLR3-CLEC18A 和 TLR3-CLEC18A(S339R) 复合物与聚 (I:C) 的结合亲和力进一步增加。此外，响应聚 (I:C) 或 H5N1 甲型流感病毒 (IAV) 感染，CLEC18A 和 CLEC18A(S339R) 会增强 I 型和 III 型干扰素 (IFN) 的产生，但不会增强促炎细胞因子。与野生型 (WT) 小鼠相比，ROSA-CLEC18A 和 ROSA-CLEC18A(S339R) 小鼠产生更高量的干扰素，并且对 H5N1 IAV 感染具有更强的抵抗力。因此，CLEC18A 是一种 TLR3 共受体，可能导致人和小鼠之间对聚 (I:C) 和 IAV 感染的免疫反应存在差异。