Miles Brodie, Miller Shannon M, Connick Elizabeth
Division of Infectious Diseases, University of Colorado Denver , Aurora, CO , USA.
Department of Immunology, University of Colorado Denver , Aurora, CO , USA.
Front Immunol. 2016 Dec 27;7:659. doi: 10.3389/fimmu.2016.00659. eCollection 2016.
T follicular helper cells (T) are a specialized subset of CD4 T cells that reside in B cell follicles and promote B cell maturation into plasma cells and long-lived memory B cells. During chronic infection prior to the development of AIDS, HIV-1 (HIV) replication is largely concentrated in T. Paradoxically, T numbers are increased in early and midstages of disease, thereby promoting HIV replication and disease progression. Despite increased T numbers, numerous defects in humoral immunity are detected in HIV-infected individuals, including dysregulation of B cell maturation, impaired somatic hypermutation, and low quality of antibody production despite hypergammaglobulinemia. Clinically, these defects are manifested by increased vulnerability to bacterial infections and impaired vaccine responses, neither of which is fully reversed by antiretroviral therapy (ART). Deficits in T function, including reduced HIV-specific IL-21 production and low levels of co-stimulatory receptor expression, have been linked to these immune impairments. Impairments in T likely contribute as well to the ability of HIV to persist and evade humoral immunity, particularly the inability to develop broadly neutralizing antibodies. In addition to direct infection of T, other mechanisms that have been linked to T deficits in HIV infection include upregulation of PD-L1 on germinal center B cells and augmented follicular regulatory T cell responses. Challenges to development of strategies to enhance T function in HIV infection include lack of an established phenotype for memory T as well as limited understanding of the relationship between peripheral T and lymphoid tissue T. Interventions to augment T function in HIV-infected individuals could enhance immune reconstitution during ART and potentially augment cure strategies.
滤泡辅助性T细胞（Tfh）是CD4 T细胞的一个特殊亚群，存在于B细胞滤泡中，促进B细胞成熟为浆细胞和长寿记忆B细胞。在艾滋病发展之前的慢性感染期间，HIV-1（艾滋病毒）复制主要集中在Tfh细胞中。矛盾的是，在疾病的早期和中期，Tfh细胞数量增加，从而促进艾滋病毒复制和疾病进展。尽管Tfh细胞数量增加，但在艾滋病毒感染个体中检测到体液免疫存在许多缺陷，包括B细胞成熟失调、体细胞超突变受损以及尽管存在高丙种球蛋白血症但抗体产生质量低下。临床上，这些缺陷表现为易受细菌感染和疫苗反应受损，抗逆转录病毒疗法（ART）均不能完全逆转这两种情况。Tfh细胞功能缺陷，包括艾滋病毒特异性IL-21产生减少和共刺激受体表达水平低下，与这些免疫损伤有关。Tfh细胞功能受损也可能导致艾滋病毒持续存在和逃避免疫的能力，特别是无法产生广泛中和抗体。除了直接感染Tfh细胞外，与艾滋病毒感染中Tfh细胞缺陷相关的其他机制包括生发中心B细胞上PD-L1的上调和滤泡调节性T细胞反应增强。在艾滋病毒感染中增强Tfh细胞功能策略的开发面临的挑战包括缺乏记忆Tfh细胞的既定表型以及对外周Tfh细胞和淋巴组织Tfh细胞之间关系的了解有限。在艾滋病毒感染个体中增强Tfh细胞功能的干预措施可以增强ART期间的免疫重建，并可能增强治愈策略。
