Boer Mardi C, Prins Corine, van Meijgaarden Krista E, van Dissel Jaap T, Ottenhoff Tom H M, Joosten Simone A
Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands National Institute for Public Health and the Environment, RIVM, Bilthoven, The Netherlands.
Clin Vaccine Immunol. 2015 Jul;22(7):778-88. doi: 10.1128/CVI.00162-15. Epub 2015 May 6.
Mycobacterium bovis bacillus Calmette-Guérin (BCG), the only currently available vaccine against tuberculosis, induces variable protection in adults. Immune correlates of protection are lacking, and analyses on cytokine-producing T cell subsets in protected versus unprotected cohorts have yielded inconsistent results. We studied the primary T cell response, both proinflammatory and regulatory T cell responses, induced by BCG vaccination in adults. Twelve healthy adult volunteers who were tuberculin skin test (TST) negative, QuantiFERON test (QFT) negative, and BCG naive were vaccinated with BCG and followed up prospectively. BCG vaccination induced an unexpectedly dichotomous immune response in this small, BCG-naive, young-adult cohort: BCG vaccination induced either gamma interferon-positive (IFN-γ(+)) interleukin 2-positive (IL-2(+)) tumor necrosis factor α-positive (TNF-α(+)) polyfunctional CD4(+) T cells concurrent with CD4(+) IL-17A(+) and CD8(+) IFN-γ(+) T cells or, in contrast, virtually absent cytokine responses with induction of CD8(+) regulatory T cells. Significant induction of polyfunctional CD4(+) IFN-γ(+) IL-2(+) TNF-α(+) T cells and IFN-γ production by peripheral blood mononuclear cells (PBMCs) was confined to individuals with strong immunization-induced local skin inflammation and increased serum C-reactive protein (CRP). Conversely, in individuals with mild inflammation, regulatory-like CD8(+) T cells were uniquely induced. Thus, BCG vaccination either induced a broad proinflammatory T cell response with local inflammatory reactogenicity or, in contrast, a predominant CD8(+) regulatory T cell response with mild local inflammation, poor cytokine induction, and absent polyfunctional CD4(+) T cells. Further detailed fine mapping of the heterogeneous host response to BCG vaccination using classical and nonclassical immune markers will enhance our understanding of the mechanisms and determinants that underlie the induction of apparently opposite immune responses and how these impact the ability of BCG to induce protective immunity to TB.
牛分枝杆菌卡介苗（BCG）是目前唯一可用的抗结核疫苗，在成年人中诱导的保护作用存在差异。缺乏保护的免疫相关指标，并且对受保护队列与未受保护队列中产生细胞因子的T细胞亚群的分析结果并不一致。我们研究了卡介苗接种在成年人中诱导的主要T细胞反应，包括促炎和调节性T细胞反应。12名结核菌素皮肤试验（TST）阴性、全血γ干扰素释放试验（QFT）阴性且未接种过卡介苗的健康成年志愿者接种了卡介苗，并进行前瞻性随访。在这个未接种过卡介苗的年轻成年小队列中，卡介苗接种诱导了意想不到的二分免疫反应：卡介苗接种要么诱导γ干扰素阳性（IFN-γ(+)）、白细胞介素2阳性（IL-2(+)）、肿瘤坏死因子α阳性（TNF-α(+)）的多功能CD4(+) T细胞，同时伴有CD4(+) IL-17A(+)和CD8(+) IFN-γ(+) T细胞；或者相反，几乎没有细胞因子反应，但诱导产生了CD8(+)调节性T细胞。多功能CD4(+) IFN-γ(+) IL-2(+) TNF-α(+) T细胞的显著诱导以及外周血单核细胞（PBMC）产生IFN-γ仅限于那些有强烈免疫诱导的局部皮肤炎症且血清C反应蛋白（CRP）升高的个体。相反，在炎症较轻的个体中，独特地诱导产生了调节样CD8(+) T细胞。因此，卡介苗接种要么诱导具有局部炎症反应性的广泛促炎T细胞反应，要么相反，诱导主要的CD8(+)调节性T细胞反应，伴有轻度局部炎症、细胞因子诱导不良且缺乏多功能CD4(+) T细胞。使用经典和非经典免疫标志物对卡介苗接种的异质性宿主反应进行进一步详细的精细定位，将增进我们对诱导明显相反免疫反应的机制和决定因素的理解，以及这些因素如何影响卡介苗诱导对结核病保护性免疫的能力。
