Department of Pediatrics, University of Colorado-Denver Anschutz Medical Campus, Aurora, CO, United States.
Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado-Denver Anschutz Medical Campus, Aurora, CO, United States.
Front Immunol. 2022 Aug 12;13:960313. doi: 10.3389/fimmu.2022.960313. eCollection 2022.
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. experiments showed that NK IFNγ expression depended on APC cytokine secretion in response to TLR stimulation. 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.
HIV 暴露未感染婴儿（HEU）在前 6 个月的生命中由于感染而导致发病率和死亡率增加，这种情况在 2 岁时逐渐减少。潜在的免疫缺陷仍然未被定义。我们通过比较未刺激的 APC 表型、对 Toll 样受体（TLR）刺激的反应以及在 1-2 天生命（出生）的 24 名 HEU 和 64 名 HIV 未暴露婴儿（HUU）以及 6 个月生命的 28 名 HEU 和 45 名 HUU 中激活自然杀伤（NK）细胞的能力，研究了抗原呈递细胞（APC）。在出生时，与 HUU 相比，未刺激的 APC 在 HEU 中表现出更高水平的激活和细胞因子产生，而 TLR 激动剂的刺激显示 HEU 中的 APC 表达更低水平的炎症细胞因子和激活标志物，但表达相似的 IL10 调节细胞因子。这些差异在 6 个月时仍然存在。从出生到 6 个月，APC 在 HUU 中经历了广泛的表型和功能变化，而在 HEU 中变化很小。TLR 刺激也导致 HEU 中 NK 细胞表达 CD69 和/或 IFNγ的水平低于 HUU，无论是在出生时还是在 6 个月时。体外实验表明，NK IFNγ的表达取决于 APC 在 TLR 刺激下对细胞因子分泌的反应。IL10 补充减少了 APC 介导的 NK 细胞激活，通过 IFNγ的表达来衡量。我们得出结论，与 HUU 相比，HEU 在生命的前 6 个月中 APC 的成熟受到阻碍或延迟。HEU 中炎症 APC 反应不足和/或炎症和调节反应之间的不平衡可能在其对严重感染的易感性增加中发挥重要作用。
