Multifunctional CD4 Cells Expressing Gamma Interferon and Perforin Mediate Protection against Lethal Influenza Virus Infection
Multifunctional CD4 Cells Expressing Gamma Interferon and Perforin Mediate Protection against Lethal Influenza Virus Infection
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DOI：
10.1128/jvi.07172-11
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发表时间：
2012-06-01
影响因子：
5.4
通讯作者：
Swain, Susan L.
中科院分区：
文献类型：
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作者：
Brown, Deborah M.;Lee, Sarah;Swain, Susan L.
体外产生的CD 4效应物可以通过涉及II类限制性穿孔素介导的细胞毒性的抗体非依赖性机制促进针对高致病性流感病毒的存活。然而，尚不清楚在流感病毒感染期间活化的CD 4细胞是否可以获得有助于保护免受致死性攻击的细胞溶解活性。从受感染小鼠的肺中分离的CD 4细胞能够提供针对致死剂量的H1N1流感病毒A/波多黎各8/34（PR 8）的保护。用PR 8感染BALB/c小鼠诱导多功能CD 4群体，其具有增殖能力和在引流淋巴结（DLN）中分泌白细胞介素-2（IL-2）和肿瘤坏死因子α（TNF-α）以及在肺中分泌γ干扰素（IFN-γ）和IL-10的能力。与野生型（WT）CD 4细胞相比，IFN-γ缺陷型CD 4细胞产生更大量的IL-17和相似水平的TNF-α、IL-10和IL-2。WT和IFN-γ（-/-）CD 4细胞均表现出流感病毒特异性细胞毒性;然而，IFN-γ缺陷型CD 4细胞在致死感染后不能像WT CD 4细胞那样有效地促进恢复。PR 8感染诱导了一群细胞溶解性CD 4效应物，这些效应物存在于肺中，但不在DLN中。这些细胞表达颗粒酶B（GrB），并需要穿孔素来裂解肽脉冲靶。与给予WT流感病毒特异性CD 4细胞的小鼠相比，给予缺乏穿孔素的流感病毒特异性CD 4细胞的致死性感染小鼠表现出更大的体重减轻和更慢的恢复时间。综上所述，这些数据加强了CD 4 T细胞效应子广泛多功能的概念，其在促进针对致死性流感病毒感染的保护中具有直接作用。
CD4 effectors generated in vitro can promote survival against a highly pathogenic influenza virus via an antibody-independent mechanism involving class II-restricted, perforin-mediated cytotoxicity. However, it is not known whether CD4 cells activated during influenza virus infection can acquire cytolytic activity that contributes to protection against lethal challenge. CD4 cells isolated from the lungs of infected mice were able to confer protection against a lethal dose of H1N1 influenza virus A/Puerto Rico 8/34 (PR8). Infection of BALB/c mice with PR8 induced a multifunctional CD4 population with proliferative capacity and ability to secrete interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF-alpha) in the draining lymph node (DLN) and gamma interferon (IFN-gamma) and IL-10 in the lung. IFN-gamma-deficient CD4 cells produced larger amounts of IL-17 and similar levels of TNF-alpha, IL-10, and IL-2 compared to wild-type (WT) CD4 cells. Both WT and IFN-gamma(-/-) CD4 cells exhibit influenza virus-specific cytotoxicity; however, IPN-gamma-deficient CD4 cells did not promote recovery after lethal infection as effectively as WT CD4 cells. PR8 infection induced a population of cytolytic CD4 effectors that resided in the lung but not the DLN. These cells expressed granzyme B (GrB) and required perforin to lyse peptide-pulsed targets. Lethally infected mice given influenza virus-specific CD4 cells deficient in perforin showed greater weight loss and a slower time to recovery than mice given WT influenza virus-specific CD4 cells. Taken together, these data strengthen the concept that CD4 T cell effectors are broadly multifunctional with direct roles in promoting protection against lethal influenza virus infection.