TLR2-dependent induction of IL-10 and Foxp3+ CD25+ CD4+ regulatory T cells prevents effective anti-tumor immunity induced by Pam2 lipopeptides in vivo.
TLR2-dependent induction of IL-10 and Foxp3+ CD25+ CD4+ regulatory T cells prevents effective anti-tumor immunity induced by Pam2 lipopeptides in vivo.
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DOI：
10.1371/journal.pone.0018833
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发表时间：
2011-04-20
期刊：
影响因子：
3.7
通讯作者：
Seya T
中科院分区：
文献类型：
--
作者：
Yamazaki S;Okada K;Maruyama A;Matsumoto M;Yagita H;Seya T
16 S-[2，3-双（棕榈酰）丙基]半胱氨酸（Pam 2）脂肽作为Toll样受体（TLR）2/6配体，在体外激活自然杀伤（NK）细胞和树突状细胞（DC）以产生炎性细胞因子和细胞毒性NK活性。然而，在这项研究中，我们发现全身注射Pam 2脂肽对抑制NK敏感的B16黑色素瘤在体内是无效的。当我们研究免疫抑制机制时，全身注射Pam 2脂肽以TLR 2依赖性方式诱导IL-10。Pam 2脂肽以TLR 2和IL-10依赖性方式增加Foxp 3 + CD 4+调节性T（T reg）细胞的频率。来自注射Pam 2-脂肽的小鼠的T reg细胞保持抑制活性。与单独的Pam 2脂肽相比，Pam 2脂肽加上用抗CD 25单克隆抗体耗尽T reg改善了肿瘤生长。总之，我们的数据表明，全身治疗的Pam 2脂肽促进IL-10的生产和T reg功能，这抑制了有效的诱导抗肿瘤免疫在体内。有必要开发一种在体内不促进IL-10和T reg功能的佐剂，以用于将来建立抗癌疫苗。
16 S-[2,3-bis(palmitoyl)propyl]cysteine (Pam2) lipopeptides act as toll-like receptor (TLR)2/6 ligands and activate natural killer (NK) cells and dendritic cells (DCs) to produce inflammatory cytokines and cytotoxic NK activity in vitro. However, in this study, we found that systemic injection of Pam2 lipopeptides was not effective for the suppression of NK-sensitive B16 melanomas in vivo. When we investigated the immune suppressive mechanisms, systemic injection of Pam2 lipopeptides induced IL-10 in a TLR2-dependent manner. The Pam2 lipopeptides increased the frequencies of Foxp3+CD4+ regulatory T (T reg) cells in a TLR2- and IL-10- dependent manner. The T reg cells from Pam2-lipopeptide injected mice maintained suppressor activity. Pam2 lipopeptides, plus the depletion of T reg with an anti-CD25 monoclonal antibody, improved tumor growth compared with Pam2 lipopeptides alone. In conclusion, our data suggested that systemic treatment of Pam2 lipopeptides promoted IL-10 production and T reg function, which suppressed the effective induction of anti-tumor immunity in vivo. It is necessary to develop an adjuvant that does not promote IL-10 and T reg function in vivo for the future establishment of an anti-cancer vaccine.
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