Abudulai Laila N, Fernandez Sonia, Corscadden Karli, Burrows Sally A, Hunter Michael, Tjiam M Christian, Kirkham Lea-Ann S, Post Jeffrey J, French Martyn A
School of Pathology & Laboratory Medicine, The University of Western Australia, Perth, Australia.
Center for Vaccine and Infectious Disease Research, Telethon Kids Institute, The University of Western Australia, Perth, Australia.
PLoS One. 2017 May 2;12(5):e0176641. doi: 10.1371/journal.pone.0176641. eCollection 2017.
Dysfunction of T follicular-helper (TFH) cells is a possible cause of impaired germinal centre (GC) and IgG antibody responses in individuals with human immunodeficiency virus-1 (HIV-1) infection and might contribute to decreased magnitude and isotype diversification of IgG antibodies to pneumococcal polysaccharides (PcPs). We examined the production of IgG1 and IgG2 antibodies to PcPs 4, 6B, 9V and 14 by enumerating antibody secreting cells (ASCs) at day (D) 7 and determining fold-increase in serum antibody levels at D28 after vaccination with unconjugated PcPs in HIV seronegative subjects (n = 20) and in HIV patients who were receiving antiretroviral therapy (ART) (n = 28) or who were ART-naive (n = 11) and determined their association with ICOS+ and ICOS- circulating memory TFH (cmTFH) cells (CD4+CD45RA-CD27+CXCR5+PD-1+) and short lived plasmablasts (SPBs) at D7, and with PcP-specific and total IgM+ and IgG+ memory B cells at D0. In HIV seronegative subjects, production of IgG1+ and IgG2+ ASCs was consistently associated with the frequency of ICOS+ cmTFH cells but not ICOS- cmTFH cells or memory B cells. In contrast, post-vaccination ASCs in HIV patients, regardless of ART status, were lower than in HIV seronegative subjects and not associated with ICOS+ cmTFH cells, the expansion of which was absent (ART-naive patients) or much lower than in HIV seronegative subjects (ART-treated patients). Production of SPBs was also lower in ART-naive patients. Fold-increase in IgG2 antibodies at D28 also correlated with ICOS+ cmTFH cells at D7 in HIV seronegative subjects but not in HIV patients. These novel findings provide evidence that ICOS+ cmTFH cells contribute to the regulation of PcP-specific IgG antibody responses, including isotype diversification, and that TFH cell dysfunction may be a cause of impaired PcP-specific IgG antibody responses and increased susceptibility to pneumococcal disease in HIV patients.
滤泡辅助性T（TFH）细胞功能障碍可能是导致人类免疫缺陷病毒1型（HIV-1）感染者生发中心（GC）和IgG抗体反应受损的原因之一，并且可能导致针对肺炎球菌多糖（PcP）的IgG抗体数量减少和同种型多样化受损。我们通过在第7天（D7）计数抗体分泌细胞（ASC）并在未结合的PcP疫苗接种后第28天（D28）测定血清抗体水平的增加倍数，来检测HIV血清阴性受试者（n = 20）、接受抗逆转录病毒治疗（ART）的HIV患者（n = 28）或未接受ART治疗的HIV患者（n = 11）针对PcP 4、6B、9V和14产生IgG1和IgG2抗体的情况，并确定它们与D7时ICOS +和ICOS -循环记忆TFH（cmTFH）细胞（CD4 + CD45RA - CD27 + CXCR5 + PD-1 +）和短命浆母细胞（SPB）以及D0时PcP特异性和总IgM +和IgG +记忆B细胞的关联。在HIV血清阴性受试者中，IgG1 +和IgG2 + ASC的产生始终与ICOS + cmTFH细胞的频率相关，而与ICOS - cmTFH细胞或记忆B细胞无关。相比之下，无论ART状态如何，HIV患者接种疫苗后的ASC均低于HIV血清阴性受试者，并且与ICOS + cmTFH细胞无关，ICOS + cmTFH细胞的扩增在未接受ART治疗的患者中不存在或远低于HIV血清阴性受试者（接受ART治疗的患者）。未接受ART治疗的患者中SPB的产生也较低。D28时IgG2抗体的增加倍数在HIV血清阴性受试者中也与D7时的ICOS + cmTFH细胞相关，但在HIV患者中则不然。这些新发现提供了证据，表明ICOS + cmTFH细胞有助于调节PcP特异性IgG抗体反应，包括同种型多样化，并且TFH细胞功能障碍可能是HIV患者中PcP特异性IgG抗体反应受损和肺炎球菌疾病易感性增加的原因。
