Université Paris Descartes, 75270 Paris, France.
Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10632-7. doi: 10.1073/pnas.1000027107. Epub 2010 May 24.
HIV-1 infection is characterized by a progressive decline in CD4(+) T cells leading to a state of profound immunodeficiency. IL-2 therapy has been shown to improve CD4(+) counts beyond that observed with antiretroviral therapy. Recent phase III trials revealed that despite a sustained increase in CD4(+) counts, IL-2-treated patients did not experience a better clinical outcome [Abrams D, et al. (2009) N Engl J Med 361(16):1548-1559]. To explain these disappointing results, we have studied phenotypic, functional, and molecular characteristics of CD4(+) T cell populations in IL-2-treated patients. We found that the principal effect of long-term IL-2 therapy was the expansion of two distinct CD4(+)CD25(+) T cell populations (CD4(+)CD25(lo)CD127(lo)FOXP3(+) and CD4(+)CD25(hi)CD127(lo)FOXP3(hi)) that shared phenotypic markers of Treg but could be distinguished by the levels of CD25 and FOXP3 expression. IL-2-expanded CD4(+)CD25(+) T cells suppressed proliferation of effector cells in vitro and had gene expression profiles similar to those of natural regulatory CD4(+)CD25(hi)FOXP3(+) T cells (Treg) from healthy donors, an immunosuppressive T cell subset critically important for the maintenance of self-tolerance. We propose that the sustained increase of the peripheral Treg pool in IL-2-treated HIV patients may account for the unexpected clinical observation that patients with the greatest expansion of CD4(+) T cells had a higher relative risk of clinical progression to AIDS.
HIV-1 感染的特征是 CD4(+) T 细胞逐渐减少，导致严重免疫缺陷。IL-2 治疗已被证明可提高 CD4(+)计数，超过抗逆转录病毒治疗所观察到的效果。最近的 III 期试验表明，尽管 CD4(+)计数持续增加，IL-2 治疗的患者并未获得更好的临床结果 [Abrams D, 等人。(2009)N Engl J Med 361(16):1548-1559]。为了解释这些令人失望的结果，我们研究了 IL-2 治疗患者的 CD4(+) T 细胞群体的表型、功能和分子特征。我们发现，长期 IL-2 治疗的主要作用是扩大两个不同的 CD4(+)CD25(+) T 细胞群体（CD4(+)CD25(lo)CD127(lo)FOXP3(+)和 CD4(+)CD25(hi)CD127(lo)FOXP3(hi))，它们具有 Treg 的表型标志物，但可以通过 CD25 和 FOXP3 表达水平来区分。IL-2 扩增的 CD4(+)CD25(+) T 细胞在体外抑制效应细胞的增殖，并且具有与来自健康供体的天然调节性 CD4(+)CD25(hi)FOXP3(+) T 细胞（Treg）相似的基因表达谱，这是维持自身耐受至关重要的免疫抑制性 T 细胞亚群。我们提出，IL-2 治疗的 HIV 患者外周 Treg 池的持续增加可能是导致意外临床观察的原因，即 CD4(+) T 细胞扩增最大的患者发生 AIDS 临床进展的相对风险更高。
