Agostini C, Trentin L, Sancetta R, Facco M, Tassinari C, Cerutti A, Bortolin M, Milani A, Siviero M, Zambello R, Semenzato G
Department of Clinical and Experimental Medicine, Padua University School of Medicine, Italy.
Blood. 1997 Aug 1;90(3):1115-23.
The impairment of interleukin-2 (IL-2) production occurs very early after human immunodeficiency virus (HIV) infection as a consequence of the quantitative depletion of Th1 cells. Despite the shift in cytokine production, most individuals develop an oligoclonal expansion of major histocompatibility complex restricted, HIV-specific CD8+ cytotoxic T lymphocytes (CTL) in different organs, suggesting that other cytokines replace IL-2 in initiating the tissue infiltration of CD8+ T cells. In this study we show that IL-15, a product of monocyte-macrophages and non-T cells and which has overlapping biological activities with IL-2, is involved in local cell networks accounting for the activation and expansion of CD8+ T-cell pools in a highly affected organ, ie, the lung. IL-15 induced proliferation of T cells obtained from the lower respiratory tract of HIV-infected patients with T-cell alveolitis and severe depletion of CD4+ T cells. Lung lymphocytes were CD45R0+/CD8+ T cells spontaneously expressing activation markers (CD69 and HLA-DR) and equipped with the receptorial subunits which bind IL-15, notably the beta and gamma chains of the IL-2 receptor (IL-2R) and the recently identified IL-15 binding-protein termed IL-15R alpha. Similar phenotypic findings were obtained after incubation of normal T cells with IL-15, which induced CD8+ T cells to express activation markers and to proliferate. The block of the IL-2R beta/IL-2R gamma complex with specific monoclonal antibodies abolished the T-cell stimulatory activity of IL-15 while the combination of IL-15 and tumor necrosis factor-alpha upregulated the proliferative response of lung T lymphocytes. The hypothesis that the tissue growth of lung CD8+ lymphocytes may involve cytokines produced from cells other than T lymphocytes was confirmed by the evidence that pulmonary macrophages expressed high levels of IL-15 and that anti-IL-15 antibodies inhibited the accessory function of alveolar macrophages on mitogen-induced CD8+ T-cell proliferation. Together, these results suggest that macrophage-derived cytokines produced at sites of T-cell infiltration play a role in the activation of HIV-specific CD8+ T-cell-mediated immune response.
人类免疫缺陷病毒（HIV）感染后，由于Th1细胞数量减少，白细胞介素-2（IL-2）的产生很早就受到损害。尽管细胞因子产生发生了变化，但大多数个体在不同器官中出现了主要组织相容性复合体受限的寡克隆性HIV特异性CD8+细胞毒性T淋巴细胞（CTL）扩增，这表明其他细胞因子在启动CD8+ T细胞的组织浸润中取代了IL-2。在本研究中，我们表明IL-15，一种单核细胞-巨噬细胞和非T细胞的产物，与IL-2具有重叠的生物学活性，参与了局部细胞网络，该网络负责在一个受影响严重的器官即肺中CD8+ T细胞池的激活和扩增。IL-15诱导了从患有T细胞肺泡炎和CD4+ T细胞严重耗竭的HIV感染患者下呼吸道获得的T细胞增殖。肺淋巴细胞是自发表达激活标志物（CD69和HLA-DR）的CD45R0+/CD8+ T细胞，并配备了结合IL-15的受体亚基，特别是IL-2受体（IL-2R）的β链和γ链以及最近鉴定的称为IL-15Rα的IL-15结合蛋白。用IL-15孵育正常T细胞后也获得了类似的表型结果，IL-15诱导CD8+ T细胞表达激活标志物并增殖。用特异性单克隆抗体阻断IL-2Rβ/IL-2Rγ复合体消除了IL-15的T细胞刺激活性，而IL-15和肿瘤坏死因子-α的组合上调了肺T淋巴细胞的增殖反应。肺巨噬细胞表达高水平的IL-15以及抗IL-15抗体抑制肺泡巨噬细胞对丝裂原诱导的CD8+ T细胞增殖的辅助功能，这些证据证实了肺CD8+淋巴细胞的组织生长可能涉及T淋巴细胞以外的细胞产生的细胞因子这一假说。总之，这些结果表明在T细胞浸润部位产生的巨噬细胞衍生细胞因子在HIV特异性CD8+ T细胞介导的免疫反应激活中发挥作用。
