Fogle Jonathan E, Mexas Angela M, Tompkins Wayne A, Tompkins Mary B
Department of Population Health and Pathobiology, North Carolina State University College of Veterinary Medicine , Raleigh, NC 27606, USA.
AIDS Res Hum Retroviruses. 2010 Feb;26(2):201-16. doi: 10.1089/aid.2009.0162.
CD8(+) lymphocytes are critical to the control and elimination of viral pathogens. Impaired CD8(+) responses are well recognized in lentiviral infections; however, the mechanisms underlying CD8(+) impairment remain elusive. Using the feline immunodeficiency virus (FIV) model for human AIDS, we reported previously that CD4(+)CD25(+) Treg cells in both the acute and long-term, asymptomatic phase of infection are constitutively activated and suppress CD4(+)CD25(-) T cell responses. In the current study, we have demonstrated that CD4(+)CD25(+) Treg cells suppress CD8(+) responses to immune stimulation during both the acute and chronic, asymptomatic phase of FIV infection and that the mechanism of suppression may be mediated by membrane-associated TGF-beta (mTGF-beta) on CD4(+)CD25(+) lymphocytes. Depletion of CD4(+)CD25(+) lymphocytes from lymph node suspensions significantly enhanced production of IFN-gamma during the acute phase of infection and coculture of CD8(+) lymphocytes with CD4(+)CD25(+) lymphocytes resulted in suppression of CD8(+) IFN-gamma during both the acute and chronic stages of infection. FACS analysis indicated that there was TGF-betaRII upregulation on CD8(+) cells from FIV(+) cats during the acute and chronic stage of infection. In addition, there was upregulation of mTGF-beta on the CD4(+)CD25(+) subset in chronically infected cats. In support of activation of the TGF-beta signaling pathway, Western blotting showed Smad 2 phosphorylation in CD8(+) targets following CD4(+)CD25(+)/CD8(+) coculture. These results demonstrate the suppressive effect CD4(+)CD25(+) Treg cells have on the CD8(+) immune response during the acute and chronic stages of FIV infection and suggest that the mechanism of suppression may be mediated by mTGF-beta.
CD8(+)淋巴细胞对于控制和清除病毒病原体至关重要。在慢病毒感染中，CD8(+)反应受损已得到充分认识；然而，CD8(+)受损的潜在机制仍不清楚。利用猫免疫缺陷病毒（FIV）作为人类艾滋病的模型，我们先前报道在感染的急性期和长期无症状期，CD4(+)CD25(+)调节性T细胞均被持续激活，并抑制CD4(+)CD25(-)T细胞反应。在当前研究中，我们证明在FIV感染的急性期和慢性无症状期，CD4(+)CD25(+)调节性T细胞均抑制CD8(+)对免疫刺激的反应，且抑制机制可能由CD4(+)CD25(+)淋巴细胞上的膜相关转化生长因子-β（mTGF-β）介导。从淋巴结悬液中去除CD4(+)CD25(+)淋巴细胞可显著增强感染急性期干扰素-γ的产生，并且CD8(+)淋巴细胞与CD4(+)CD25(+)淋巴细胞共培养导致在感染的急性期和慢性期CD8(+)干扰素-γ均受到抑制。流式细胞术分析表明，在感染的急性期和慢性期，来自FIV(+)猫的CD8(+)细胞上转化生长因子-β受体II（TGF-βRII）上调。此外，在慢性感染猫的CD4(+)CD25(+)亚群中mTGF-β上调。为支持转化生长因子-β信号通路的激活，蛋白质印迹法显示CD4(+)CD25(+)/CD8(+)共培养后CD8(+)靶细胞中Smad 2磷酸化。这些结果证明CD4(+)CD25(+)调节性T细胞在FIV感染的急性期和慢性期对CD8(+)免疫反应具有抑制作用，并提示抑制机制可能由mTGF-β介导。
