T-bet:Eomes balance, effector function, and proliferation of cytomegalovirus-specific CD8+ T cells during primary infection differentiates the capacity for durable immune control.
T-bet:Eomes balance, effector function, and proliferation of cytomegalovirus-specific CD8+ T cells during primary infection differentiates the capacity for durable immune control.
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DOI：
10.4049/jimmunol.1401436
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发表时间：
2014-12-01
期刊：
影响因子：
--
通讯作者：
McDyer JF
中科院分区：
文献类型：
--
作者：
Popescu I;Pipeling MR;Shah PD;Orens JB;McDyer JF
巨细胞病毒（CMV）仍然是实体器官移植，特别是肺移植受者（LTR）的重要机会致病菌。与CMV不匹配的LTR（供体+/受体-; D+R-）是活动性CMV感染和死亡率增加的高风险，但病毒控制的免疫相关性仍不完全清楚。我们前瞻性研究了原发性CMV感染期间的23个D+R− LTR，以确定急性CD 8 + T细胞参数是否区分早期慢性感染中病毒控制的能力。T-bet > Eomes的T-box转录因子表达模式将LTR控制者与病毒血症复发者区分开来，并且Eomes与颗粒酶B载量和CMV磷蛋白65（pp 65）特异性CD 8 +IFN-γ+和CD 107 a+频率相关。与LTR控制者相比，LTR复发者表现出离体CD 8 + Ki 67+细胞减少，并且在第6天时显著损害了CD 8 + pp 65特异性体外增殖应答，伴随着较低的pp 65特异性CD 4 +IL-2+频率。然而，CMV特异性体外增殖反应可以被显著挽救，最有效地与pp 65抗原和外源性IL-2，导致增加的T-bet：Eomes平衡，并增强效应子功能。使用I类CMV四聚体，我们观察到复发者和控制者之间相似的频率，尽管复发者的四聚体+细胞中T-bet：Eomes平衡降低，沿着受损的CD 8+效应子对四聚体-肽再刺激的应答。总之，这些数据表明CMV特异性CD 8+效应子应答受损并不是因为完全缺乏CMV特异性细胞，而是强调了T-bet：Eomes平衡的重要性，CMV特异性增殖是在原发感染期间驱动CD 8 + T细胞中早期T-bet表达和效应子功能的关键因素，并区分了高风险LTR在早期慢性感染期间建立免疫控制的能力。
CMV remains an important opportunistic pathogen in solid organ transplantation, particularly in lung transplant recipients (LTRs). LTRs mismatched for CMV (donor+/recipient−; D+R−) are at high-risk for active CMV infection and increased mortality, however the immune correlates of viral control remain incompletely understood. We prospectively studied 23 D+R− LTRs during primary CMV infection to determine whether acute CD8+ T-cell parameters differentiated the capacity for viral control in early chronic infection. T-box transcription factors expression patterns of T-bet > Eomes differentiated LTR controllers from viremic relapsers, and reciprocally correlated with granzyme B loading, and CMV phosphoprotein 65 (pp65)-specific CD8+IFN-γ+ and CD107a+ frequencies. LTR relapsers demonstrated reduced CD8+Ki67+ cells ex vivo and substantially impaired CD8+pp65-specific in vitro proliferative responses at 6 days, with concomitantly lower pp65-specific CD4+IL-2+ frequencies, as compared to LTR controllers. However, CMV-specific in vitro proliferative responses could be significantly rescued, most effectively with pp65 antigen and exogenous IL-2, resulting in an increased T-bet:Eomes balance, and enhanced effector function. Using class I CMV tetramers, we observed similar frequencies between relapsers and controllers, though reduced T-bet:Eomes balance in tetramer+ cells from relapsers, along with impaired CD8+ effector responses to tetramer-peptide restimulation. Together, these data show impaired CMV-specific CD8+ effector responses is not for complete lack of CMV-specific cells, but rather, underscores the importance of the T-bet:Eomes balance, with CMV-specific proliferation a key factor driving early T-bet expression and effector function in CD8+ T cells during primary infection, and differentiating the capacity of high-risk LTRs to establish immune control during early chronic infection.
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