Cook Kevin D, Kline Hannah C, Whitmire Jason K
*Department of Genetics and Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
*Department of Genetics and Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
J Leukoc Biol. 2015 Aug;98(2):153-62. doi: 10.1189/jlb.4HI1214-594R. Epub 2015 May 18.
There is a need to understand better how to improve B cell responses and immunity to persisting virus infections, which often cause debilitating illness or death. People with chronic virus infection show evidence of improved virus control when there is a strong neutralizing antibody response, and conversely, B cell dysfunction is associated with higher viral loads. We showed previously that NK cells inhibit CD4(+) and CD8(+) T cell responses to disseminating LCMV infection and that depletion of NK cells attenuates chronic infection. Here, we examined the effect of NK cell depletion on B cell responses to LCMV infection in mice. Whereas mice infected acutely generated a peak level of antibody soon after the infection was resolved, mice infected chronically showed a continued increase in antibody levels that exceeded those after acute infection. We found that early NK cell depletion rapidly increased virus-specific antibody levels to chronic infection, and this effect depended on CD4(+) T cells and was associated with elevated numbers of CXCR5(+)CD4(+) TFH cells. However, the NK cell-depleted mice controlled the infection and by 1 mo pi, had lower TFH cell numbers and antibody levels compared with mice with sustained infection. Finally, we show that NK cell depletion improved antiviral CD8(+) T cell responses only when B cells and virus-specific antibody were present. Our data indicate that NK cells diminish immunity to chronic infection, in part, by suppressing TFH cell and antibody responses.
有必要更好地了解如何改善B细胞反应以及对持续病毒感染的免疫力，这些感染常常导致使人虚弱的疾病或死亡。慢性病毒感染患者在产生强烈的中和抗体反应时，会出现病毒控制改善的迹象，反之，B细胞功能障碍与更高的病毒载量相关。我们之前表明，自然杀伤细胞（NK细胞）会抑制CD4(+)和CD8(+) T细胞对播散性淋巴细胞脉络丛脑膜炎病毒（LCMV）感染的反应，并且NK细胞的耗竭会减轻慢性感染。在此，我们研究了NK细胞耗竭对小鼠B细胞对LCMV感染反应的影响。急性感染的小鼠在感染消退后不久会产生抗体峰值水平，而慢性感染的小鼠则显示抗体水平持续升高，超过急性感染后的水平。我们发现，早期NK细胞耗竭会迅速提高对慢性感染的病毒特异性抗体水平，这种效应依赖于CD4(+) T细胞，并且与CXCR5(+)CD4(+)滤泡辅助性T细胞（TFH细胞）数量增加有关。然而，与持续感染的小鼠相比，NK细胞耗竭的小鼠控制了感染，并且在感染后1个月时，TFH细胞数量和抗体水平较低。最后，我们表明，只有当B细胞和病毒特异性抗体存在时，NK细胞耗竭才会改善抗病毒CD8(+) T细胞反应。我们的数据表明，NK细胞部分通过抑制TFH细胞和抗体反应来削弱对慢性感染的免疫力。
