Seder R A, Grabstein K H, Berzofsky J A, McDyer J F
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Exp Med. 1995 Oct 1;182(4):1067-77. doi: 10.1084/jem.182.4.1067.
Cytokines have been shown to be powerful regulators of the immune response. In this study, we analyze the effect that the newly recognized cytokine interleukin (IL)-15 has on proliferation and cytokine induction using peripheral blood mononuclear cells (PBMCs) and purified CD4+ T cells from patients infected with human immunodeficiency virus (HIV) who are at various stages in their disease. We observed that IL-15 enhances the proliferative response in a dose-dependent manner from PBMCs of HIV-infected individuals when stimulated by polyclonal mitogen, tetanus toxoid, or HIV-specific antigen. The effects of exogenous IL-15 are substantially diminished by adding a neutralizing antibody to the beta chain of the IL-2 receptor. Moreover, the ability of IL-15 to increase proliferation is enhanced by the presence of endogenous IL-2 produced in the cultures. The effect that exogenous IL-15 had on IL-2, IL-4, and interferon (IFN)-gamma induction from PBMC's or CD4+ T cells in response to mitogen or tetanus toxoid was also examined. This was compared to the effect that exogenous IL-2 and IL-12 had under the same conditions. Addition of IL-2 or IL-15 to short-term in vitro cultures of either PBMCs or CD4+ T cells had little effect on IL-2, IL-4, or IFN-gamma production. By contrast, IL-12 caused substantial enhancement of both IL-2 and IFN-gamma production from these cultures. The role that endogenous cytokines have on IFN-gamma induction was also studied. Addition of a neutralizing antibody to the alpha chain of the IL-2 receptor or IL-12 to antigen stimulated cultures caused a striking decrease in IFN-gamma production. Neutralization of endogenous IL-15 also resulted in diminished IFN-gamma production from cultures stimulated with mitogen. IL-4 and IFN-gamma protein production by PBMCs and CD4+ T cells stimulated with mitogen was assessed to see if we could detect a specific bias of cytokine production. Small amounts of IL-4 were detected from CD4+ T cells but not PBMCs from most individuals tested. IFN-gamma and IL-2, however, were also produced from these same cultures. These results further elucidate the mechanism of cytokine regulation in HIV-infected individuals, and they provide evidence that IL-15 may be a useful immune modulator.
细胞因子已被证明是免疫反应的强大调节因子。在本研究中，我们使用来自感染人类免疫缺陷病毒（HIV）且处于疾病不同阶段患者的外周血单核细胞（PBMC）和纯化的CD4 + T细胞，分析新发现的细胞因子白细胞介素（IL）-15对增殖和细胞因子诱导的影响。我们观察到，当受到多克隆有丝分裂原、破伤风类毒素或HIV特异性抗原刺激时，IL-15以剂量依赖的方式增强HIV感染个体PBMC的增殖反应。通过向IL-2受体的β链添加中和抗体，外源性IL-15的作用会显著减弱。此外，培养物中产生的内源性IL-2会增强IL-15增加增殖的能力。我们还研究了外源性IL-15对PBMC或CD4 + T细胞在有丝分裂原或破伤风类毒素刺激下诱导IL-2、IL-4和干扰素（IFN）-γ的影响。并将其与相同条件下外源性IL-2和IL-12的作用进行比较。向PBMC或CD4 + T细胞的短期体外培养物中添加IL-2或IL-15对IL-2、IL-4或IFN-γ的产生影响很小。相比之下，IL-12可显著增强这些培养物中IL-2和IFN-γ的产生。我们还研究了内源性细胞因子对IFN-γ诱导的作用。向抗原刺激的培养物中添加IL-2受体α链的中和抗体或IL-12会导致IFN-γ产生显著减少。内源性IL-15被中和也会导致有丝分裂原刺激的培养物中IFN-γ产生减少。我们评估了有丝分裂原刺激的PBMC和CD4 + T细胞产生的IL-4和IFN-γ蛋白，以确定是否能检测到细胞因子产生的特定偏差。在大多数测试个体的CD4 + T细胞中检测到少量IL-4，但PBMC中未检测到。然而，这些相同的培养物也产生IFN-γ和IL-2。这些结果进一步阐明了HIV感染个体中细胞因子调节的机制，并提供了证据表明IL-15可能是一种有用的免疫调节剂。
