Chaudhri Geeta, Tahiliani Vikas, Eldi Preethi, Karupiah Gunasegaran
Department of Immunology, The John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Department of Immunology, The John Curtin School of Medical Research, Australian National University, Canberra, Australia
J Virol. 2015 Feb;89(3):1889-99. doi: 10.1128/JVI.02572-14. Epub 2014 Nov 26.
Antibody production by B cells in the absence of CD4 T cell help has been shown to be necessary and sufficient for protection against secondary orthopoxvirus (OPV) infections. This conclusion is based on short-term depletion of leukocyte subsets in vaccinated animals, in addition to passive transfer of immune serum to naive hosts that are subsequently protected from lethal orthopoxvirus infection. Here, we show that CD4 T cell help is necessary for neutralizing antibody production and virus control during a secondary ectromelia virus (ECTV) infection. A crucial role for CD4 T cells was revealed when depletion of this subset was extended beyond the acute phase of infection. Sustained depletion of CD4 T cells over several weeks in vaccinated animals during a secondary infection resulted in gradual diminution of B cell responses, including neutralizing antibody, contemporaneous with a corresponding increase in the viral load. Long-term elimination of CD8 T cells alone delayed virus clearance, but prolonged depletion of both CD4 and CD8 T cells resulted in death associated with uncontrolled virus replication. In the absence of CD4 T cells, perforin- and granzyme A- and B-dependent effector functions of CD8 T cells became critical. Our data therefore show that both CD4 T cell help for antibody production and CD8 T cell effector function are critical for protection against secondary OPV infection. These results are consistent with the notion that the effectiveness of the smallpox vaccine is related to its capacity to induce both B and T cell memory.
Smallpox eradication through vaccination is one of the most successful public health endeavors of modern medicine. The use of various orthopoxvirus (OPV) models to elucidate correlates of vaccine-induced protective immunity showed that antibody is critical for protection against secondary infection, whereas the role of T cells is unclear. Short-term leukocyte subset depletion in vaccinated animals or transfer of immune serum to naive, immunocompetent hosts indicates that antibody alone is necessary and sufficient for protection. We show here that long-term depletion of CD4 T cells over several weeks in vaccinated animals during secondary OPV challenge reveals an important role for CD4 T cell-dependent antibody responses in effective virus control. Prolonged elimination of CD8 T cells alone delayed virus clearance, but depletion of both T cell subsets resulted in death associated with uncontrolled virus replication. Thus, vaccinated individuals who subsequently acquire T cell deficiencies may not be protected against secondary OPV infection.
已证明B细胞在无CD4 T细胞辅助的情况下产生抗体对于预防继发性正痘病毒（OPV）感染是必要且充分的。这一结论基于对已接种疫苗动物的白细胞亚群进行短期清除，以及将免疫血清被动转移至随后受到致死性正痘病毒感染保护的未接触过病原体的宿主。在此，我们表明在继发性埃可病毒（ECTV）感染期间，CD4 T细胞辅助对于中和抗体产生和病毒控制是必要的。当该亚群的清除时间延长至感染急性期之后时，CD4 T细胞的关键作用得以显现。在继发性感染期间，对已接种疫苗的动物持续数周清除CD4 T细胞，导致B细胞反应逐渐减弱，包括中和抗体，同时病毒载量相应增加。单独长期清除CD8 T细胞会延迟病毒清除，但同时长期清除CD4和CD8 T细胞会导致与病毒复制失控相关的死亡。在缺乏CD4 T细胞的情况下，CD8 T细胞的穿孔素、颗粒酶A和B依赖性效应功能变得至关重要。因此，我们的数据表明，CD4 T细胞对抗体产生的辅助作用以及CD8 T细胞的效应功能对于预防继发性OPV感染均至关重要。这些结果与天花疫苗的有效性与其诱导B细胞和T细胞记忆的能力相关这一观点一致。
通过接种疫苗根除天花是现代医学最成功的公共卫生成就之一。使用各种正痘病毒（OPV）模型来阐明疫苗诱导的保护性免疫的相关因素表明，抗体对于预防继发性感染至关重要，而T细胞的作用尚不清楚。对已接种疫苗的动物进行短期白细胞亚群清除或向未接触过病原体的有免疫能力的宿主转移免疫血清表明，仅抗体对于保护是必要且充分的。我们在此表明，在继发性OPV攻击期间，对已接种疫苗的动物持续数周长期清除CD4 T细胞揭示了CD4 T细胞依赖性抗体反应在有效病毒控制中的重要作用。单独长期清除CD8 T细胞会延迟病毒清除，但清除两个T细胞亚群会导致与病毒复制失控相关的死亡。因此，随后获得T细胞缺陷的已接种疫苗个体可能无法预防继发性OPV感染。
