Table_2_FoxP3+ CD8 T-cells in acute HIV infection and following early antiretroviral therapy initiation.docx

ObjectivesBesides CD4 regulatory T-cells (Tregs), immunosuppressor FoxP3+ CD8 T-cells are emerging as an important subset of Tregs, which contribute to immune dysfunction and disease progression in HIV infection. However, FoxP3+ CD8 T-cell dynamics in acute HIV infection and following early antiretroviral therapy (ART) initiation remain understudied.
MethodsSubsets of FoxP3+ CD8 T-cells were characterized both prospectively and cross-sectionally in PBMCs from untreated acute (n=26) and chronic (n=10) HIV-infected individuals, early ART-treated in acute infection (n=10, median of ART initiation: 5.5 months post-infection), ART-treated in chronic infection (n=10), elite controllers (n=18), and HIV-uninfected controls (n=21).
ResultsAcute and chronic infection were associated with increased total, effector memory, and terminally differentiated FoxP3+ CD8 T-cells, while early ART normalized only the frequencies of total FoxP3+ CD8 T-cells. We observed an increase in FoxP3+ CD8 T-cell immune activation (HLADR+/CD38+), senescence (CD57+/CD28-), and PD-1 expression during acute and chronic infection, which were not normalized by early ART. FoxP3+ CD8 T-cells in untreated participants expressed higher levels of immunosuppressive LAP(TGF-β1) and CD39 than uninfected controls, whereas early ART did not affect their expression. The expression of gut-homing markers CCR9 and Integrin-β7 by total FoxP3+ CD8 T-cells and CD39+ and LAP(TGF-β1)+ FoxP3+ CD8 T-cells increased in untreated individuals and remained higher than in uninfected controls despite early ART. Elite controllers share most of the FoxP3+ CD8 T-cell characteristics in uninfected individuals.
ConclusionsAlthough early ART normalized total FoxP3+ CD8 T-cells frequencies, it did not affect the persistent elevation of the gut-homing potential of CD39+ and LAP(TGF-β1)+ FoxP3+ CD8 T-cell, which may contribute to immune dysfunction.

研究目的 除CD4调节性T细胞（CD4 regulatory T-cells）外，免疫抑制性FoxP3阳性CD8+T细胞（FoxP3+ CD8 T-cells）正逐渐成为一类重要的调节性T细胞亚群，其参与HIV感染过程中的免疫功能紊乱与疾病进展。然而，急性HIV感染阶段以及早期启动抗逆转录病毒治疗（antiretroviral therapy, ART）后，FoxP3阳性CD8+T细胞的动态变化仍未得到充分研究。
研究方法 本研究采用前瞻性与横断面分析相结合的方式，对以下人群外周血单个核细胞（peripheral blood mononuclear cells, PBMCs）中的FoxP3阳性CD8+T细胞亚群进行表征：未接受治疗的急性HIV感染者（n=26）、慢性HIV感染者（n=10）、急性感染后早期启动抗逆转录病毒治疗者（n=10，抗逆转录病毒治疗中位启动时间为感染后5.5个月）、慢性感染抗逆转录病毒治疗者（n=10）、HIV感染精英控制者（n=18）以及HIV阴性对照者（n=21）。
研究结果 急性与慢性HIV感染均会导致总FoxP3阳性CD8+T细胞、效应记忆性FoxP3阳性CD8+T细胞以及终末分化FoxP3阳性CD8+T细胞的比例升高；早期抗逆转录病毒治疗仅能使总FoxP3阳性CD8+T细胞的频率恢复至正常水平。本研究观察到，急性与慢性感染阶段，FoxP3阳性CD8+T细胞的免疫激活状态（HLA-DR+/CD38+）、衰老表型（CD57+/CD28-）以及PD-1表达水平均显著升高，且早期抗逆转录病毒治疗无法使这些指标恢复正常。未接受治疗的感染者体内，FoxP3阳性CD8+T细胞的免疫抑制分子LAP(TGF-β1)与CD39的表达水平显著高于HIV阴性对照者，而早期抗逆转录病毒治疗并未对这两种分子的表达产生影响。总FoxP3阳性CD8+T细胞以及CD39阳性、LAP(TGF-β1)阳性FoxP3阳性CD8+T细胞的肠道归巢标志物CCR9与整合素β7（Integrin-β7）的表达水平在未治疗个体中显著升高，即便接受早期抗逆转录病毒治疗，其表达水平仍高于HIV阴性对照者。HIV感染精英控制者的FoxP3阳性CD8+T细胞特征与HIV阴性个体基本一致。
研究结论 尽管早期抗逆转录病毒治疗可使总FoxP3阳性CD8+T细胞的频率恢复正常，但无法逆转CD39阳性与LAP(TGF-β1)阳性FoxP3阳性CD8+T细胞肠道归巢潜能的持续升高，这一现象可能是HIV感染后免疫功能紊乱的潜在诱因之一。