Special Centre for Molecular Medicine (SCMM), Jawaharlal Nehru University, New Delhi, India.
International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
PLoS Pathog. 2020 Sep 21;16(9):e1008887. doi: 10.1371/journal.ppat.1008887. eCollection 2020 Sep.
Despite the availability of multiple antibiotics, tuberculosis (TB) remains a major health problem worldwide, with one third of the population latently infected and ~2 million deaths annually. The only available vaccine for TB, Bacillus Calmette Guérin (BCG), is ineffective against adult pulmonary TB. Therefore, alternate strategies that enhance vaccine efficacy are urgently needed. Vaccine efficacy and long-term immune memory are critically dependent on central memory T (TCM) cells, whereas effector memory T (TEM) cells are important for clearing acute infections. Recently, it has been shown that inhibition of the Kv1.3 K+ ion channel, which is predominantly expressed on TEM but not TCM cells, profoundly enhances TCM cell differentiation. We exploited this phenomenon to improve TCM:TEM cell ratios and protective immunity against Mycobacterium tuberculosis infection in response to BCG vaccination of mice. We demonstrate that luteolin, a plant-derived Kv1.3 K+ channel inhibitor, profoundly promotes TCM cells by selectively inhibiting TEM cells, and significantly enhances BCG vaccine efficacy. Thus, addition of luteolin to BCG vaccination may provide a sustainable means to improve vaccine efficacy by boosting host immunity via modulation of memory T cell differentiation.
尽管有多种抗生素可供使用，但结核病（TB）仍然是全球范围内的一个主要健康问题，全球约有三分之一的人口感染了潜伏性结核，每年有 200 万人死于结核病。目前唯一可用的结核病疫苗卡介苗（BCG）对成人肺结核无效。因此，迫切需要增强疫苗效力的替代策略。疫苗效力和长期免疫记忆取决于中央记忆 T（TCM）细胞，而效应记忆 T（TEM）细胞对于清除急性感染很重要。最近，已经表明，抑制主要在 TEM 细胞而不是 TCM 细胞上表达的 Kv1.3 K+离子通道，可极大地促进 TCM 细胞分化。我们利用这一现象来改善 TCM：TEM 细胞比值，并提高对结核分枝杆菌感染的保护性免疫，以响应 BCG 疫苗接种的小鼠。我们证明，木犀草素是一种植物源性 Kv1.3 K+通道抑制剂，通过选择性抑制 TEM 细胞，极大地促进了 TCM 细胞的产生，并显著增强了 BCG 疫苗的效力。因此，在 BCG 疫苗接种中加入木犀草素可能是一种可持续的方法，通过调节记忆 T 细胞分化来增强宿主免疫力，从而提高疫苗效力。
