Smith Christiana, Jalbert Emilie, de Almeida Volia, Canniff Jennifer, Lenz Laurel L, Mussi-Pinhata Marisa M, Cohen Rachel A, Yu Qilu, Amaral Fabiana R, Pinto Jorge, Alarcon Jorge O, Siberry George, Weinberg Adriana
Department of Pediatric Infectious Diseases, University of Colorado School of Medicine, Aurora, CO, USA.
Federal University of Sao Carlos Biological and Health Sciences Center, Sao Carlos, Brazil.
Front Immunol. 2017 Apr 24;8:470. doi: 10.3389/fimmu.2017.00470. eCollection 2017.
HIV-exposed uninfected (HEU) infants have higher rates of severe and fatal infections compared with HIV-unexposed (HUU) infants, likely due to immune perturbations. We hypothesized that alterations in natural killer (NK) cell activity might occur in HEU infants and predispose them to severe infections.
Case-control study using cryopreserved peripheral blood mononuclear cells (PBMCs) at birth and 6 months from HEU infants enrolled from 2002 to 2009 and HUU infants enrolled from 2011 to 2013.
NK cell phenotype and function were assessed by flow cytometry after 20-h incubation with and without K562 cells.
The proportion of NK cells among PBMCs was lower at birth in 12 HEU vs. 22 HUU (1.68 vs. 10.30%, < 0.0001) and at 6 months in 52 HEU vs. 72 HUU (3.09 vs. 4.65%, = 0.0005). At birth, HEU NK cells demonstrated increased killing of K562 target cells ( < 0.0001) and increased expression of CD107a (21.65 vs. 12.70%, = 0.047), but these differences resolved by 6 months. Stimulated HEU NK cells produced less interferon (IFN)γ at birth (0.77 vs. 2.64%, = 0.008) and at 6 months (4.12 vs. 8.39%, = 0.001), and showed reduced perforin staining at 6 months (66.95 vs. 77.30%, = 0.0008). Analysis of cell culture supernatants indicated that lower NK cell activity in HEU was associated with reduced interleukin (IL)-12, IL-15, and IL-18. Addition of recombinant human IL-12 to stimulated HEU PBMCs restored IFNγ production to that seen in stimulated HUU cultures.
NK cell proportion, phenotype, and function are altered in HEU infants. NK cell cytotoxicity and degranulation are increased in HEU at birth, but HEU NK cells have reduced IFNγ and perforin production, suggesting an adequate initial response, but decreased functional reserve. NK cell function improved with addition of exogenous IL-12, implicating impaired production of IL-12 by accessory cells. Alterations in NK cell and accessory cell function may contribute to the increased susceptibility to infection in HEU infants.
与未接触HIV（HUU）的婴儿相比，暴露于HIV但未感染（HEU）的婴儿发生严重和致命感染的几率更高，这可能是由于免疫紊乱所致。我们推测，HEU婴儿可能会出现自然杀伤（NK）细胞活性改变，并使其易发生严重感染。
采用病例对照研究，使用2002年至2009年入组的HEU婴儿以及2011年至2013年入组的HUU婴儿出生时和6个月时冻存的外周血单个核细胞（PBMC）。
在有和没有K562细胞的情况下孵育20小时后，通过流式细胞术评估NK细胞表型和功能。
12例HEU婴儿出生时PBMC中NK细胞比例低于22例HUU婴儿（1.68%对10.30%，P<0.0001），52例HEU婴儿6个月时低于72例HUU婴儿（3.09%对4.65%，P = 0.0005）。出生时，HEU NK细胞对K562靶细胞的杀伤作用增强（P<0.0001），CD107a表达增加（21.65%对12.70%，P = 0.047），但这些差异在6个月时消失。出生时及6个月时，受刺激的HEU NK细胞产生的干扰素（IFN）γ较少（出生时：0.77%对2.64%，P = （此处原文有误，推测为0.008）；6个月时：4.12%对8.39%，P = 0.001），6个月时穿孔素染色减少（66.95%对77.30%，P = 0.0008）。细胞培养上清液分析表明，HEU中较低的NK细胞活性与白细胞介素（IL）-12、IL-15和IL-18减少有关。向受刺激的HEU PBMC中添加重组人IL-12可使IFNγ产生恢复至受刺激的HUU培养物中的水平。
HEU婴儿的NK细胞比例、表型和功能发生改变。出生时HEU的NK细胞细胞毒性和脱颗粒增加，但HEU NK细胞的IFNγ和穿孔素产生减少，提示初始反应充分，但功能储备下降。添加外源性IL-12可改善NK细胞功能，提示辅助细胞产生IL-12受损。NK细胞和辅助细胞功能的改变可能导致HEU婴儿感染易感性增加。
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