CD4 T-Cell Help Programs a Change in CD8 T-Cell Function Enabling Effective Long-Term Control of Murine Gammaherpesvirus 68: Role of PD-1-PD-L1 Interactions
CD4 T-Cell Help Programs a Change in CD8 T-Cell Function Enabling Effective Long-Term Control of Murine Gammaherpesvirus 68: Role of PD-1-PD-L1 Interactions
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DOI：
10.1128/jvi.00784-10
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发表时间：
2010-08-15
影响因子：
5.4
通讯作者：
Sarawar, Sally R.
中科院分区：
文献类型：
--
作者：
Dias, Peter;Giannoni, Francesca;Sarawar, Sally R.
我们先前表明，CD 40的激动性抗体可以替代CD 4 T细胞的帮助，并防止小鼠γ疱疹病毒68（MHV-68）在主要组织相容性复合体（MHC）II类-/-（CII-/-）小鼠（CD 4 T细胞缺乏）肺中的再活化。虽然这种效应需要CD 8 T细胞，但在体外检测到其活性没有变化。一个关键问题是抗CD 40治疗（或CD 4 T细胞帮助）是否改变了体内CD 8 T细胞或其他细胞类型的功能。为了解决这个问题，在本研究中，我们表明，过继转移的CD 8 T细胞从病毒感染的野生型小鼠或抗CD 40治疗的CII-/-小鼠引起肺病毒滴度显着降低，与对照CII-/-小鼠。抗CD 40治疗也大大延长了受感染的CII-/-小鼠的生存期。这证实了共刺激信号引起CD 8 T细胞的变化，使其能够维持对MHV-68的有效长期控制。我们研究了这种变化的性质，发现与野生型或CD 28/CTLA 4（-/-）小鼠相比，MHV-68感染的CII-/-、CD 40（-/-）或CD 80/86（-/-）小鼠肺中CD 8 T细胞上抑制性受体PD-1的表达显著增加，与病毒再活化水平相关。此外，阻断PD-1-PD-L1相互作用显著降低了CD 4 T细胞缺陷小鼠中的病毒再活化。相反，另一种抑制性受体NKG 2A的缺失没有影响。这些数据表明，CD 4 T细胞帮助编程改变由PD-1表达改变介导的CD 8 T细胞功能，这使得能够有效地长期控制MHV-68。
We previously showed that agonistic antibodies to CD40 could substitute for CD4 T-cell help and prevent reactivation of murine gammaherpesvirus 68 (MHV-68) in the lungs of major histocompatibility complex (MHC) class II-/- (CII-/-) mice, which are CD4 T cell deficient. Although CD8 T cells were required for this effect, no change in their activity was detected in vitro. A key question was whether anti-CD40 treatment (or CD4 T-cell help) changed the function of CD8 T cells or another cell type in vivo. To address this question, in the present study, we showed that adoptive transfer of CD8 T cells from virus-infected wild-type mice or anti-CD40-treated CII-/- mice caused a significant reduction in lung viral titers, in contrast to those from control CII-/- mice. Anti-CD40 treatment also greatly prolonged survival of infected CII-/- mice. This confirms that costimulatory signals cause a change in CD8 T cells enabling them to maintain effective long-term control of MHV-68. We investigated the nature of this change and found that expression of the inhibitory receptor PD-1 was significantly increased on CD8 T cells in the lungs of MHV-68-infected CII-/-, CD40(-/-), or CD80/86(-/-) mice, compared with that in wild-type or CD28/CTLA4(-/-) mice, correlating with the level of viral reactivation. Furthermore, blocking PD-1-PD-L1 interactions significantly reduced viral reactivation in CD4 T-cell-deficient mice. In contrast, the absence of another inhibitory receptor, NKG2A, had no effect. These data suggest that CD4 T-cell help programs a change in CD8 T-cell function mediated by altered PD-1 expression, which enables effective long-term control of MHV-68.