Immunoadjuvant effects of polyadenylic:polyuridylic acids through TLR3 and TLR7.
Immunoadjuvant effects of polyadenylic:polyuridylic acids through TLR3 and TLR7.
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DOI：
10.1093/intimm/dxm112
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发表时间：
2008
影响因子：
4.4
通讯作者：
T. Sugiyama;K. Hoshino;M. Saito;T. Yano;I. Sasaki;C. Yamazaki;S. Akira;T. Kaisho
中科院分区：
文献类型：
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作者：
T. Sugiyama;K. Hoshino;M. Saito;T. Yano;I. Sasaki;C. Yamazaki;S. Akira;T. Kaisho
双链RNA （dsRNA）在病毒感染时产生，可以激活先天免疫。polyinosic:polycytidylic acids [poly(I:C)]是一种合成的dsRNA模拟物，通过内体受体、toll样受体（TLR） 3或细胞质受体发挥作用。另一种类型的dsRNA， polyadenylic:polyuridylic acids [poly(A:U)]，也可以作为免疫佐剂，但目前尚不清楚它是如何发挥其佐剂作用的。本文对聚（A:U）的佐剂作用进行了表征。Poly（A:U）可诱导小鼠骨髓树突状细胞（dc）产生ifn - α和IL-12p40。Poly（A:U）诱导的ifn - α的产生依赖于DC亚群浆细胞样树突状细胞（pDC），并且需要TLR7。poly（A:U）刺激的pDC也以tlr7依赖的方式产生IL-12p40。除了pDC外，常规树突状细胞（cDC）也在poly（A:U）的作用下产生IL-12p40。这种IL-12p40诱导来自两个cDC亚群，CD24（高）cDC和CD11b（高）cDC，分别以TLR3-和tlr7依赖的方式。体内注射抗原poly（A:U）导致抗原特异性CD8(+) T细胞克隆扩增和ifn - γ产生。与体外研究结果一致，克隆t细胞扩增需要TLR3和TLR7。值得注意的是，TLR3，而不是TLR7，是产生ifn - γ产生CD8(+) T细胞的关键。poly（A:U）诱导的CD8(+) t细胞应答不依赖于I型IFN信号。我们的研究结果表明poly（A:U）主要通过TLR3和TLR7在体内发挥免疫佐剂的作用。
Double-stranded RNA (dsRNA) is produced upon viral infection and can activate innate immunity. Polyinosinic:polycytidylic acids [poly(I:C)] is a synthetic mimetic of dsRNA and functions through an endosomal receptor, Toll-like receptor (TLR) 3 or cytosolic receptors. Another type of dsRNA, polyadenylic:polyuridylic acids [poly(A:U)], can also act as an immune adjuvant, but it remains unclear how it exhibits its adjuvant effects. Here, we have characterized the adjuvant effects of poly(A:U). Poly(A:U) could induce both IFN-alpha and IL-12p40 from murine bone marrow dendritic cells (DCs). Poly(A:U)-induced IFN-alpha production depended on a DC subset, plasmacytoid dendritic cell (pDC), and required TLR7. IL-12p40 was also produced by poly(A:U)-stimulated pDC in a TLR7-dependent manner. In addition to pDC, conventional dendritic cell (cDC) also produced IL-12p40 in response to poly(A:U). This IL-12p40 induction resulted from two cDC subsets, CD24(high) cDC and CD11b(high) cDC in a TLR3- and TLR7-dependent manner, respectively. In vivo injection of poly(A:U) with antigen led to clonal expansion of and IFN-gamma production from antigen-specific CD8(+) T cells. Consistent with the in vitro findings, TLR3 and TLR7 were required for the clonal T-cell expansion. Notably, TLR3, rather than TLR7, was critical for generating IFN-gamma-producing CD8(+) T cells. CD8(+) T-cell responses induced by poly(A:U) were independent of type I IFN signaling. Our results demonstrate that poly(A:U) functions as an in vivo immunoadjuvant mainly through TLR3 and TLR7.