Nasi Aikaterini, Amu Sylvie, Göthlin Mårten, Jansson Marianne, Nagy Noemi, Chiodi Francesca, Réthi Bence
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Department of Laboratory Medicine, Lund University, Lund, Sweden.
Front Immunol. 2017 Mar 13;8:244. doi: 10.3389/fimmu.2017.00244. eCollection 2017.
Dendritic cells (DCs) are potent antigen-presenting cells that might play contradictory roles during HIV-1 infection, contributing not only to antiviral immunity but also to viral dissemination and immune evasion. Although DCs are characterized by enormous functional diversity, it has not been analyzed how differentially programmed DCs interact with HIV-1. We have previously described the reprogramming of DC development by endogenously produced lactic acid that accumulated in a cell culture density-dependent manner and provided a long-lasting anti-inflammatory signal to the cells. By exploiting this mechanism, we generated immunostimulatory DCs characterized by the production of TH1 polarizing and inflammatory mediators or, alternatively, suppressed DCs that produce IL-10 upon activation, and we tested the interaction of these DC types with different HIV-1 strains. Cytokine patterns were monitored in HIV-1-exposed DC cultures. Our results showed that DCs receiving suppressive developmental program strongly upregulated their capacity to produce the TH1 polarizing cytokine IL-12 and the inflammatory chemokines CCL2 and CCL7 upon interaction with HIV-1 strains IIIB and SF162. On the contrary, HIV-1 abolished cytokine production in the more inflammatory DC types. Preincubation of the cells with the HIV-1 proteins gp120 and Nef could inhibit IL-12 production irrespectively of the tested DC types, whereas MyD88- and TRIF-dependent signals stimulated IL-12 production in the suppressed DC type only. Rewiring of DC cytokines did not require DC infections or ligation of the HIV-1 receptor CD209. A third HIV-1 strain, BaL, could not modulate DC cytokines in a similar manner indicating that individual HIV-1 strains can differ in their capacity to influence DCs. Our results demonstrated that HIV-1 could not induce definite and invariable modulatory programs in DCs. Instead, interaction with the virus triggered different responses in different DC types. Thus, the outcome of DC-HIV-1 interactions might be highly variable, shaped by endogenous features of the cells and diversity of the virus.
树突状细胞（DCs）是强大的抗原呈递细胞，在HIV-1感染过程中可能发挥相互矛盾的作用，不仅有助于抗病毒免疫，还会促进病毒传播和免疫逃逸。尽管DCs具有巨大的功能多样性，但尚未分析不同程序设定的DCs如何与HIV-1相互作用。我们之前描述过，内源性产生的乳酸以细胞培养密度依赖性方式积累，并为细胞提供持久的抗炎信号，从而对DC发育进行重编程。通过利用这一机制，我们生成了具有免疫刺激作用的DCs，其特征是产生TH1极化和炎症介质，或者生成激活后产生IL-10的抑制性DCs，并测试了这些DC类型与不同HIV-1毒株的相互作用。在暴露于HIV-1的DC培养物中监测细胞因子模式。我们的结果表明，接受抑制性发育程序的DCs在与HIV-1毒株IIIB和SF162相互作用时，会强烈上调其产生TH1极化细胞因子IL-12以及炎症趋化因子CCL2和CCL7的能力。相反，HIV-1会消除更具炎症性的DC类型中的细胞因子产生。用HIV-1蛋白gp120和Nef对细胞进行预孵育，无论测试的DC类型如何，均可抑制IL-12的产生，而依赖MyD88和TRIF的信号仅在抑制性DC类型中刺激IL-12的产生。DC细胞因子的重新编程不需要DC感染或HIV-1受体CD209的连接。第三种HIV-1毒株BaL不能以类似方式调节DC细胞因子，这表明不同的HIV-1毒株影响DCs的能力可能不同。我们的结果表明，HIV-1不能在DCs中诱导确定且不变的调节程序。相反，与病毒的相互作用在不同的DC类型中引发了不同的反应。因此，DC-HIV-1相互作用的结果可能高度可变，由细胞的内源性特征和病毒的多样性决定。
