Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Anzio Road, Observatory, 7925 Cape Town, South Africa.
J Virol. 2011 Dec;85(24):13333-41. doi: 10.1128/JVI.05671-11. Epub 2011 Oct 12.
In blood, the accumulation of terminally differentiated (TD) T cells during HIV infection is associated with CD4 T cell loss and HIV disease progression. Here, we investigated the maintenance and functional characteristics of memory T cells at the cervix. We found that CD4 T cell depletion at the cervix mirrors CD4 depletion in blood. In all women, depletion of CD4 T cells at the cervix was associated with significant reductions in CD45RA- CCR7+ (central memory [CM]) T cells and the accumulation of CD45RA+ CCR7- (TD T cells). We determined whether inflammation in the genital tract was associated with the local differentiation of T cells at the cervix. In uninfected women, genital tract inflammation was associated with the accumulation of CD45RA- CCR7+ CM CD4 T cells and reduced frequencies of CD45RA+ CCR7- TD cells at the cervix. This finding may reflect the fact that, in the absence of HIV infection, TD T cells may be slowly lost in the presence of genital inflammation, while CD45RA- CCR7+ CM T cells are recruited to replenish the diminishing CD4 T cell pool. Following global stimulation with phorbol myristate acetate (PMA)-ionomycin, we noted a significant interleukin 2 (IL-2) deficit in both cervical and blood CD4 T cells from HIV-infected women compared to uninfected women, while gamma interferon (IFN-γ) production was similar, irrespective of HIV status. Few HIV-infected women had detectable IFN-γ and IL-2 HIV-specific T cell responses at the cervix, and these responses were significantly lower in magnitude than the corresponding responses in blood. These data suggest that CD4 depletion was associated with the accumulation of terminally differentiated T cell phenotypes at the cervical mucosa defective in their ability to produce IL-2. CD4 depletion and compromised immunity at the cervix may be accompanied by progressive decline of central memory-like T cells and development of T cells toward terminally differentiated phenotypes.
在 HIV 感染期间，血液中终末分化（TD）T 细胞的积累与 CD4 T 细胞的丧失和 HIV 疾病的进展有关。在这里，我们研究了宫颈中记忆 T 细胞的维持和功能特征。我们发现，宫颈中 CD4 T 细胞的耗竭与血液中 CD4 耗竭相吻合。在所有女性中，宫颈 CD4 T 细胞的耗竭与 CD45RA-CCR7+（中央记忆 [CM]）T 细胞的显著减少以及 CD45RA+CCR7-（TD T 细胞）的积累有关。我们确定生殖道炎症是否与宫颈 T 细胞的局部分化有关。在未感染的女性中，生殖道炎症与宫颈 CD45RA-CCR7+CM CD4 T 细胞的积累以及 CD45RA+CCR7-TD 细胞频率的降低有关。这一发现可能反映了这样一个事实，即在没有 HIV 感染的情况下，TD T 细胞可能会在生殖道炎症存在的情况下缓慢丢失，而 CD45RA-CCR7+CM T 细胞则被招募来补充不断减少的 CD4 T 细胞池。在用佛波醇 12-肉豆蔻酸 13-乙酸酯（PMA）-离子霉素进行全身刺激后，我们注意到与未感染的女性相比，HIV 感染的女性宫颈和血液 CD4 T 细胞中的白细胞介素 2（IL-2）明显不足，而γ干扰素（IFN-γ）的产生则相似，与 HIV 状态无关。少数 HIV 感染的女性在宫颈处检测到可检测的 IFN-γ和 IL-2 HIV 特异性 T 细胞反应，其反应幅度明显低于血液中的相应反应。这些数据表明，CD4 耗竭与宫颈黏膜中终末分化 T 细胞表型的积累有关，这些细胞表型在产生 IL-2 的能力上存在缺陷。CD4 耗竭和宫颈免疫功能受损可能伴随着中央记忆样 T 细胞的逐渐减少和向终末分化表型的发展。
