Borhis Gwenoline, Trovato Maria, Chaoul Nada, Ibrahim Hany M, Richard Yolande
INSERM u1016, Institut Cochin, Paris, France.
CNRS UMR 8104, Paris, France.
Front Immunol. 2017 Oct 27;8:1338. doi: 10.3389/fimmu.2017.01338. eCollection 2017.
With the goal to design effective HIV vaccines, intensive studies focused on broadly neutralizing antibodies, which arise in a fraction of HIV-infected people. Apart from identifying new vulnerability sites in the viral envelope proteins, these studies have shown that a fraction of these antibodies are produced by self/poly-reactive B-cells. These findings prompted us to revisit the B-cell differentiation and selection process during HIV/SIV infection and to consider B-cells as active players possibly shaping the helper T-cell program within germinal centers (GCs). In this context, we paid a particular attention to B-cell-activating factor (BAFF), a key cytokine in B-cell development and immune response that is overproduced during HIV/SIV infection. As it does in autoimmune diseases, BAFF excess might contribute to the abnormal rescue of self-reactive B-cells at several checkpoints of the B-cell development and impair memory B-cell generation and functions. In this review, we first point out what is known about the functions of BAFF/a proliferation-inducing ligand and their receptors [B-cell maturation, transmembrane activator and CAML interactor (TACI), and BAFF-R], in physiological and pathophysiological settings, in mice and humans. In particular, we highlight recent results on the previously underappreciated regulatory functions of TACI and on the highly regulated production of soluble TACI and BAFF-R that act as decoy receptors. In light of recent data on BAFF, TACI, and BAFF-R, we then revisit the altered phenotypes and functions of B-cell subsets during the acute and chronic phase of HIV/SIV infection. Given the atypical phenotype and reduced functions of memory B-cells in HIV/SIV infection, we particularly discuss the GC reaction, a key checkpoint where self-reactive B-cells are eliminated and pathogen-specific memory B-cells and plasmablasts/cells are generated in physiological settings. Through its capacity to differentially bind and process BAFF-R and TACI on GC B-cells and possibly on follicular helper T-cells, BAFF appears as a key regulator of the physiological GC reaction. Its local excess during HIV/SIV infection could play a key role in B-cell dysregulations.
为了设计有效的HIV疫苗，深入研究聚焦于广泛中和抗体，这类抗体出现在一小部分HIV感染者体内。除了识别病毒包膜蛋白中的新脆弱位点，这些研究还表明，这些抗体中有一部分是由自身/多反应性B细胞产生的。这些发现促使我们重新审视HIV/SIV感染期间B细胞的分化和选择过程，并将B细胞视为可能在生发中心（GCs）内塑造辅助性T细胞程序的积极参与者。在此背景下，我们特别关注B细胞激活因子（BAFF），它是B细胞发育和免疫反应中的关键细胞因子，在HIV/SIV感染期间会过度产生。正如在自身免疫性疾病中一样，BAFF过量可能在B细胞发育的多个检查点导致自身反应性B细胞异常挽救，并损害记忆B细胞的产生和功能。在这篇综述中，我们首先指出在生理和病理生理环境中，在小鼠和人类中，已知的BAFF/增殖诱导配体及其受体[B细胞成熟、跨膜激活剂和CAML相互作用分子（TACI）以及BAFF-R]的功能。特别是，我们强调了关于TACI先前未被充分认识的调节功能以及作为诱饵受体的可溶性TACI和BAFF-R的高度调节产生的最新研究结果。根据关于BAFF、TACI和BAFF-R的最新数据，我们接着重新审视HIV/SIV感染急性期和慢性期B细胞亚群的改变的表型和功能。鉴于HIV/SIV感染中记忆B细胞的非典型表型和功能降低，我们特别讨论生发中心反应，这是生理环境中消除自身反应性B细胞并产生病原体特异性记忆B细胞和浆母细胞/细胞的关键检查点。通过其在GC B细胞以及可能在滤泡辅助性T细胞上差异结合和处理BAFF-R和TACI的能力，BAFF似乎是生理生发中心反应的关键调节因子。其在HIV/SIV感染期间的局部过量可能在B细胞失调中起关键作用。
