Increased bone marrow interleukin-7 (IL-7)/IL-7R levels but reduced IL-7 responsiveness in HIV-positive patients lacking CD4+ gain on antiviral therapy.
Increased bone marrow interleukin-7 (IL-7)/IL-7R levels but reduced IL-7 responsiveness in HIV-positive patients lacking CD4+ gain on antiviral therapy.
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DOI：
10.1371/journal.pone.0015663
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发表时间：
2010-12-31
期刊：
影响因子：
3.7
通讯作者：
Marchetti G
中科院分区：
文献类型：
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作者：
Bellistrì GM;Casabianca A;Merlini E;Orlandi C;Ferrario G;Meroni L;Galli M;Magnani M;Monforte Ad;Marchetti G
骨髓 (BM) 细胞因子环境可能会严重影响 HIV 阳性个体的 T 淋巴细胞稳态。白介素 7 (IL-7) 是一种骨髓来源的细胞因子，通过 CD4+ 驱动的反馈环路调节 T 细胞稳态。 CD4+ T 淋巴细胞减少症与游离 IL-7 水平升高和 IL-7R 表达/功能降低相关，高效抗逆转录病毒治疗 (HAART) 仅可部分逆转这些情况。我们研究了 30 名接受 HAART 治疗的 HIV 阳性患者中 IL-7/IL-7Rα 的 BM 产生、外周表达和信号传导（pStat5+ 和 Bcl-2+ CD4+/CD8+ T 细胞），这些患者没有经历 CD4+ 恢复（CD4+ ≤200/μl）并且有不同水平的 HIV 病毒血症；这些患者包括 18 名免疫无反应者（INR；HIV-RNA≤50）、12 名完全失败者（CF；HIV-RNA>1000）和 23 名 HIV 血清阴性受试者。我们研究了血浆 IL-7 水平、IL-7Rα+CD4+/CD8+ T 细胞比例、PBMC 中的 IL-7Rα mRNA 表达、BM 单核细胞 (BMMC) 自发产生的 IL-7 以及 BMMC 衍生的基质细胞 (SC) 中的 IL-7 mRNA/IL-7Rα mRNA。我们还通过测量 pStat5+ 和 Bcl-2+ CD4+/CD8+ T 细胞的比例来研究 T 细胞对 IL-7 的反应性。与 HIV 血清阴性对照相比，CF 和 INR 的血浆 IL-7 水平升高，IL-7Rα CD4+/CD8+ 细胞表面表达和外周血产量降低，证实了最相关的 IL-7/IL-7R 破坏。有趣的是，BM 研究揭示了 INR 中自发 IL-7 产生较高的趋势（p = .09 与 CF），而 BMMC 衍生的基质细胞中 IL-7-Rα mRNA 水平较高的趋势不显着。然而，在 IL-7 刺激后，pStat5+CD4+ T 细胞的比例在 INR 中并未增加，尽管其组成水平较高 (p = .06)； INR 还显示出比对照更低的 Bcl-2+CD8+ T 细胞比例 (p = .04)。尽管 CD4+ T 淋巴细胞严重减少且外周 IL-7/IL-7R 谱被破坏，INR 显示 BM IL-7/IL-7Rα 表达升高，但 T 细胞对 IL-7 的反应性受损，表明旨在补充 CD4+ 区室的中枢补偿途径的活性，但这不适合通过 IL-7 受体补偿功能失调的信号传导。
The bone marrow (BM) cytokine milieu might substantially affect T-lymphocyte homeostasis in HIV-positive individuals. Interleukin-7 (IL-7) is a bone marrow-derived cytokine regulating T-cell homeostasis through a CD4+-driven feedback loop. CD4+ T-lymphopenia is associated with increased free IL-7 levels and reduced IL-7R expression/function, which are only partially reverted by highly active antiretroviral therapy (HAART). We investigated the BM production, peripheral expression and signaling (pStat5+ and Bcl-2+ CD4+/CD8+ T cells) of IL-7/IL-7Rα in 30 HAART-treated HIV-positive patients who did not experience CD4+ recovery (CD4+ ≤200/µl) and who had different levels of HIV viremia; these patients included 18 immunological nonresponders (INRs; HIV-RNA≤50), 12 complete failures (CFs; HIV-RNA>1000), and 23 HIV-seronegative subjects. We studied plasma IL-7 levels, IL-7Rα+CD4+/CD8+ T-cell proportions, IL-7Rα mRNA expression in PBMCs, spontaneous IL-7 production by BM mononuclear cells (BMMCs), and IL-7 mRNA/IL-7Rα mRNA in BMMC-derived stromal cells (SCs). We also studied T-cell responsiveness to IL-7 by measuring the proportions of pStat5+ and Bcl-2+ CD4+/CD8+ T cells. Compared to HIV-seronegative controls, CFs and INRs presented elevated plasma IL-7 levels and lower IL-7Rα CD4+/CD8+ cell-surface expression and peripheral blood production, confirming the most relevant IL-7/IL-7R disruption. Interestingly, BM investigation revealed a trend of higher spontaneous IL-7 production in INRs (p = .09 vs. CFs) with a nonsignificant trend toward higher IL-7-Rα mRNA levels in BMMC-derived stromal cells. However, upon IL-7 stimulation, the proportion of pStat5+CD4+ T cells did not increase in INRs despite higher constitutive levels (p = .06); INRs also displayed lower Bcl-2+CD8+ T-cell proportions than controls (p = .04). Despite severe CD4+ T-lymphopenia and a disrupted IL-7/IL-7R profile in the periphery, INRs display elevated BM IL-7/IL-7Rα expression but impaired T-cell responsiveness to IL-7, suggesting the activity of a central compensatory pathway targeted to replenish the CD4+ compartment, which is nevertheless inappropriate to compensate the dysfunctional signaling through IL-7 receptor.