Pušnik Jernej, Fischinger Stephanie, Dittmer Ulf, Esser Stefan, van Gils Marit J, Sanders Rogier W, Alter Galit, Streeck Hendrik
Institute of Virology, University Hospital, University of Bonn, Germany, and German Center for Infection Research (DZIF), partner site Bonn-Cologne, Germany.
Institute for HIV Research, University Hospital, University Duisburg-Essen, Essen, Germany.
J Virol. 2021 Mar 25;95(8). doi: 10.1128/JVI.02097-20. Epub 2021 Jan 27.
Antibodies with a functional Fc region were previously associated with protection from HIV-1 acquisition and spontaneous suppression of viral replication. Unlike broadly neutralizing antibodies, they are not restricted to neutralizing epitopes and do not require unconventional structural traits to exert their antiviral activity. They, therefore, develop earlier after infection and can be detected in the majority of cases. The conditions under which these antibodies are generated, however, remain largely unknown. Here we demonstrate that the generation of HIV-1 Env-specific antibodies facilitating Fc-dependent innate immune responses, including neutrophil phagocytosis (ADNP), complement deposition (ADCD), and NK cell activation, likely depends on help provided by CD4+ T and peripheral T follicular helper (pTfh) cells secreting IL-21. Other proteins, including CD40L, IFNγ, and IL-4/13, involved in crosstalk between B and T cells were linked to the production of antibodies with functional Fc region but only when co-expressed with IL-21. As a potential source of these antibodies, we identified a subset of Env-specific memory B cells known to be expanded in chronic HIV-1 infection. The frequency and level of Blimp-1 expression in Env-specific tissue-like memory B cells (TLM) correlated with the functional CD4+ T cell subsets associated with robust antibody-dependent innate responses. Thus, our data suggest a mechanism responsible for the generation of antibodies with functional Fc region in chronically HIV-1 infected individuals that is based on CD4+ T cell-induced activation of memory B cells. To develop a vaccine or immunotherapy that would cure the HIV-1 infection it is important to identify helper T cells able to mount an efficient antibody response. Here, we demonstrate that the generation of HIV-1 Env-specific antibodies facilitating antibody-dependent innate immune responses likely depends on Env-specific IL-21-secreting CD4+ T and peripheral T follicular helper cells.
具有功能性Fc区域的抗体先前被认为与预防HIV-1感染及病毒复制的自发抑制有关。与广泛中和抗体不同，它们不限于中和表位，且发挥抗病毒活性不需要非常规的结构特征。因此，它们在感染后更早产生，并且在大多数情况下都能被检测到。然而，这些抗体产生的条件在很大程度上仍然未知。在此，我们证明，促进Fc依赖性天然免疫反应（包括中性粒细胞吞噬作用（ADNP）、补体沉积（ADCD）和NK细胞活化）的HIV-1 Env特异性抗体的产生，可能依赖于分泌IL-21的CD4+ T细胞和外周滤泡辅助性T细胞（pTfh）提供的帮助。参与B细胞和T细胞相互作用的其他蛋白质，包括CD40L、IFNγ和IL-4/13，与具有功能性Fc区域的抗体产生有关，但仅在与IL-21共表达时才有关。作为这些抗体的潜在来源，我们鉴定出了在慢性HIV-1感染中已知会扩增的Env特异性记忆B细胞亚群。Env特异性组织样记忆B细胞（TLM）中Blimp-1表达的频率和水平与与强大的抗体依赖性天然反应相关的功能性CD4+ T细胞亚群相关。因此，我们的数据表明了一种在慢性HIV-1感染个体中产生具有功能性Fc区域抗体的机制，该机制基于CD4+ T细胞诱导的记忆B细胞活化。为了开发能够治愈HIV-1感染的疫苗或免疫疗法，识别能够引发有效抗体反应的辅助性T细胞很重要。在此，我们证明，促进抗体依赖性天然免疫反应的HIV-1 Env特异性抗体的产生可能依赖于分泌Env特异性IL-21的CD4+ T细胞和外周滤泡辅助性T细胞。
