Impaired functionality of antigen presenting cells in HIV- exposed uninfected infants in the first six months of life.
Impaired functionality of antigen presenting cells in HIV- exposed uninfected infants in the first six months of life.
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DOI：
10.3389/fimmu.2022.960313
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发表时间：
2022
影响因子：
7.3
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中科院分区：
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艾滋病病毒暴露未感染婴儿（HEU）在出生后的前6个月因感染导致发病率和死亡率增加，这种情况一直持续到2岁。潜在的免疫缺陷仍不明确。我们通过比较未受刺激的抗原呈递细胞（APC）的表型、对Toll样受体（TLR）刺激的反应以及激活自然杀伤（NK）细胞的能力，对24名出生1 - 2天（出生时）的HEU婴儿和64名未暴露于艾滋病病毒的婴儿（HUU）以及28名6个月大的HEU婴儿和45名HUU婴儿进行了研究。出生时，未受刺激的APC在HEU婴儿中比在HUU婴儿中表现出更高的活化水平和细胞因子产生，并且用TLR激动剂刺激后发现，与HUU婴儿相比，HEU婴儿的APC中炎症细胞因子和活化标志物的表达较低，但IL - 10调节性细胞因子的表达相似。这些差异在6个月大时仍然存在。从出生到6个月，HUU婴儿的APC发生了广泛的表型和功能变化，而HEU婴儿的变化很小。与HUU婴儿相比，在出生时和6个月时，TLR刺激在HEU婴儿中也导致NK细胞的CD69和/或干扰素γ（IFNγ）表达较低。体外实验表明，NK细胞的IFNγ表达取决于APC对TLR刺激的细胞因子分泌。体外补充IL - 10可降低通过IFNγ表达测量的APC介导的NK细胞活化。我们得出结论，与HUU婴儿相比，HEU婴儿在出生后的前6个月中APC成熟受阻或延迟。HEU婴儿炎症性APC反应不足和/或炎症与调节反应之间的失衡可能在其对严重感染易感性增加方面起重要作用。
HIV-exposed uninfected infants (HEU) have increased morbidity and mortality due to infections in the first 6 months of life that tapers down to 2 years of life. The underlying immunologic defects remain undefined. We investigated antigen-presenting cells (APC) by comparing the phenotype of unstimulated APC, responses to toll-like receptor (TLR) stimulation, and ability to activate natural killer (NK) cells in 24 HEU and 64 HIV-unexposed infants (HUU) at 1-2 days of life (birth) and 28 HEU and 45 HUU at 6 months of life. At birth, unstimulated APC showed higher levels of activation and cytokine production in HEU than HUU and stimulation with TLR agonists revealed lower expression of inflammatory cytokines and activation markers, but similar expression of IL10 regulatory cytokine, in APC from HEU compared to HUU. Differences were still present at 6 months of life. From birth to 6 months, APC underwent extensive phenotypic and functional changes in HUU and minimal changes in HEU. TLR stimulation also generated lower NK cell expression of CD69 and/or IFNγ in HEU compared with HUU at birth and 6 months. In vitro experiments showed that NK IFNγ expression depended on APC cytokine secretion in response to TLR stimulation. Ex vivo IL10 supplementation decreased APC-mediated NK cell activation measured by IFNγ expression. We conclude that APC maturation was stunted or delayed in the first 6 months of life in HEU compared with HUU. Deficient inflammatory APC responses and/or the imbalance between inflammatory and regulatory responses in HEU may play an important role in their increased susceptibility to severe infections.