Targeting human langerin promotes HIV-1 specific humoral immune responses.
Targeting human langerin promotes HIV-1 specific humoral immune responses.
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DOI：
10.1371/journal.ppat.1009749
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发表时间：
2021-07
期刊：
影响因子：
6.7
通讯作者：
Cardinaud S
中科院分区：
文献类型：
--
作者：
Kervevan J;Bouteau A;Lanza JS;Hammoudi A;Zurawski S;Surenaud M;Dieudonné L;Bonnet M;Lefebvre C;Hocini H;Marlin R;Guguin A;Hersant B;Hermeziu O;Menu E;Lacabaratz C;Lelièvre JD;Zurawski G;Godot V;Henri S;Igyártó BZ;Levy Y;Cardinaud S
开发HIV-1疫苗的主要途径仍然是诱导保护性抗体。一种基本方法是通过融合单克隆抗体（mAb）将抗原靶向到树突状细胞（DC）上的特定受体。在小鼠和非人灵长类动物模型中，用融合HIV-1 Gag抗原的抗朗格汉斯单克隆抗体靶向皮肤朗格汉斯细胞（LC）可驱动抗原特异性体液反应。这些人类免疫策略的发展需要更好地了解由人类LC驱动的早期免疫事件。因此，我们制作了与HIV-1 gp140z包膜（αLC.Env）融合的抗langerin单抗。首先，我们发现原代皮肤人LC和体外分化LC诱导naïve CD4+ T细胞分化和扩增为T滤泡辅助细胞（Tfh）。第二，当人LC用αLC预处理时。分化的Tfh细胞显著促进B细胞产生特异性IgG。引人注目的是，hiv - env特异性Ig是由hiv特异性记忆B细胞分泌的。与此一致的是，我们发现在Tfh分化和B细胞功能相关的受体和细胞因子在LC成熟和靶向Langerin后被上调。最后，我们证明了αLC对小鼠的皮下免疫作用。与非靶向性Env抗原免疫小鼠相比，Env诱导引流淋巴结中Tfh细胞、Env特异性B细胞数量和特异性IgG血清水平增加的生发中心（GC）反应。总之，我们提供的证据表明，适当靶向的人LC可以有效地诱导GC中的Tfh细胞和B细胞反应。近年来，除了“经典”疫苗载体外，还出现了基于诱导/调节和调节免疫反应的创新疫苗，目的是引发针对复杂抗原的综合T细胞和B细胞免疫反应。将抗原靶向树突状细胞是一种疫苗技术概念，得到了十多年动物模型和人体临床前实验的支持。最近的动物研究强调，朗格汉斯细胞（LC）是DC靶向疫苗方法诱导抗体反应的重要靶点。尽管如此，这些免疫策略在人类中的发展仍然难以捉摸。因此，我们开发并生产了一种通过Langerin受体特异性靶向LC的HIV候选疫苗。我们测试了我们的候选疫苗靶向皮肤外植体LC的能力和体外诱导T滤泡辅助细胞（Tfh）分化的能力。利用互补的体外模型，我们证明了人LC诱导的Tfh细胞是功能性的，我们的候选疫苗靶向LC可促进hiv感染个体的记忆B细胞分泌抗hiv IgG。在这项研究中，人类LC表现出关键的细胞功能，能够驱动有效的抗hiv -1体液反应，为原发性皮肤靶向LC的Tfh和B细胞刺激功能提供了机制证据。最后，我们在Xcr1DTA小鼠中证明了LC靶向在诱导Tfh和生发中心(GC)-B细胞和抗hiv -1抗体方面的显著优势。因此，靶向人类Langerin受体似乎是开发高效HIV-1疫苗的一种有希望的策略。
The main avenue for the development of an HIV-1 vaccine remains the induction of protective antibodies. A rationale approach is to target antigen to specific receptors on dendritic cells (DC) via fused monoclonal antibodies (mAb). In mouse and non-human primate models, targeting of skin Langerhans cells (LC) with anti-Langerin mAbs fused with HIV-1 Gag antigen drives antigen-specific humoral responses. The development of these immunization strategies in humans requires a better understanding of early immune events driven by human LC. We therefore produced anti-Langerin mAbs fused with the HIV-1 gp140z Envelope (αLC.Env). First, we show that primary skin human LC and in vitro differentiated LC induce differentiation and expansion of naïve CD4+ T cells into T follicular helper (Tfh) cells. Second, when human LC are pre-treated with αLC.Env, differentiated Tfh cells significantly promote the production of specific IgG by B cells. Strikingly, HIV-Env-specific Ig are secreted by HIV-specific memory B cells. Consistently, we found that receptors and cytokines involved in Tfh differentiation and B cell functions are upregulated by LC during their maturation and after targeting Langerin. Finally, we show that subcutaneous immunization of mice by αLC.Env induces germinal center (GC) reaction in draining lymph nodes with higher numbers of Tfh cells, Env-specific B cells, as well as specific IgG serum levels compared to mice immunized with the non-targeting Env antigen. Altogether, we provide evidence that human LC properly targeted may be licensed to efficiently induce Tfh cell and B cell responses in GC. In recent years, the place of innovative vaccines based on the induction/regulation and modulation of the immune response with the aim to elicit an integrated T- and B cell immune responses against complex antigens has emerged besides “classical” vaccine vectors. Targeting antigens to dendritic cells is a vaccine technology concept supported by more than a decade of animal models and human pre-clinical experimentation. Recent investigations in animals underscored that Langerhans cells (LC) are an important target to consider for the induction of antibody responses by DC targeting vaccine approaches. Nonetheless, the development of these immunization strategies in humans remains elusive. We therefore developed and produced an HIV vaccine candidate targeting specifically LC through the Langerin receptor. We tested the ability of our vaccine candidate of targeting LC from skin explant and of inducing in vitro the differentiation of T follicular helper (Tfh) cells. Using complementary in vitro models, we demonstrated that Tfh cells induced by human LC are functional and the targeting of LC by our vaccine candidate promotes the secretion of anti-HIV IgG by memory B cells from HIV-infected individuals. In this study human LC exhibit key cellular functions able to drive potent anti-HIV-1 humoral responses providing mechanistic evidence of the Tfh- and B cell stimulating functions of primary skin targeted LC. Finally, we demonstrated in Xcr1DTA mice the significant advantage of LC targeting for inducing Tfh and germinal center (GC)-B cells and anti-HIV-1 antibodies. Therefore, the targeting of the human Langerin receptor appears to be a promising strategy for developing efficient HIV-1 vaccine.
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DOI：
10.4049/jimmunol.1004120
发表时间：
2012-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Flacher V;Tripp CH;Haid B;Kissenpfennig A;Malissen B;Stoitzner P;Idoyaga J;Romani N
通讯作者：
Romani N
DOI：
10.4049/jimmunol.1001802
发表时间：
2010-10-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bobr A;Olvera-Gomez I;Igyarto BZ;Haley KM;Hogquist KA;Kaplan DH
通讯作者：
Kaplan DH
影响因子：
3.7
作者：
Flamar, Anne-Laure;Bonnabau, Henri;Levy, Yves
通讯作者：
Levy, Yves
影响因子：
15.9
作者：
Cheng, Liang;Wang, Qi;Su, Lishan
通讯作者：
Su, Lishan
影响因子：
32.4
作者：
Joo, HyeMee;Li, Dapeng;Dullaers, Melissa;Kim, Tae-Whan;Duluc, Dorothee;Upchurch, Katherine;Xue, Yaming;Zurawski, Sandy;Le Grand, Roger;Liu, Yong-Jun;Kuroda, Marcelo;Zurawski, Gerard;Oh, SangKon
通讯作者：
Oh, SangKon