TLR10 (CD290) Is a Regulator of Immune Responses in Human Plasmacytoid Dendritic Cells.

IF 3.6 3区 医学 Q2 IMMUNOLOGY
Pratik Deb, Sukhwinder Singh, Evelyne Kalyoussef, Nicholas J Hess, Richard I Tapping, Patricia Fitzgerald-Bocarsly
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Abstract

TLRs are the most thoroughly studied group of pattern-recognition receptors that play a central role in innate immunity. Among them, TLR10 (CD290) remains the only TLR family member without a known ligand and clearly defined functions. One major impediment to studying TLR10 is its absence in mice. A recent study on TLR10 knock-in mice demonstrated its intrinsic inhibitory role in B cells, indicating that TLR10 is a potential drug target in autoimmune diseases. In this study, we interrogated the expression and function of TLR10 in human plasmacytoid dendritic cells (pDCs). We have seen that primary human pDCs, B cells, and monocytes constitutively express TLR10. Upon preincubation with an anti-TLR10 Ab, production of cytokines in pDCs was downregulated in response to stimulation with DNA and RNA viruses. Upon further investigation into the possible mechanism, we documented phosphorylation of STAT3 upon Ab-mediated engagement of TLR10. This leads to the induction of inhibitory molecule suppressor of cytokine signaling 3 (SOCS3) expression. We have also documented the inhibition of nuclear translocation of transcription factor IFN regulatory factor 7 (IRF7) in pDCs following TLR10 engagement. Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response. Our findings indicate the potential of harnessing the function of pDCs by Ab-mediated targeting of TLR10 that may open a new therapeutic avenue for autoimmune disorders.

TLR10(CD290)是人类浆细胞树突状细胞免疫反应的调节因子
TLR 是研究得最透彻的一组模式识别受体,在先天性免疫中发挥着核心作用。其中,TLR10(CD290)仍是唯一没有已知配体和明确功能的 TLR 家族成员。研究 TLR10 的一个主要障碍是它在小鼠中的缺失。最近一项关于 TLR10 基因敲入小鼠的研究证明了它对 B 细胞的内在抑制作用,这表明 TLR10 是治疗自身免疫性疾病的潜在药物靶点。在本研究中,我们研究了 TLR10 在人类浆细胞树突状细胞(pDCs)中的表达和功能。我们发现原代人类 pDCs、B 细胞和单核细胞组成性表达 TLR10。在用抗 TLR10 抗原预孵育后,pDCs 在 DNA 和 RNA 病毒刺激下产生的细胞因子受到抑制。在进一步研究可能的机制时,我们发现在抗 TLR10 抗体介导的接合过程中,STAT3 发生了磷酸化。这导致诱导抑制分子细胞因子信号转导抑制因子 3(SOCS3)的表达。我们还记录了 TLR10 参与后 pDC 中转录因子 IFN 调节因子 7(IRF7)核转位的抑制作用。我们的数据(就我们所知)首次证明了 TLR10 在人类 pDC 表面组成性表达,并作为其先天性反应的调节因子起作用。我们的研究结果表明,通过抗体介导的 TLR10 靶向,有可能利用 pDCs 的功能,为自身免疫性疾病开辟一条新的治疗途径。
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来源期刊
Journal of immunology
Journal of immunology 医学-免疫学
CiteScore
8.20
自引率
2.30%
发文量
495
审稿时长
1 months
期刊介绍: The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)
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