Luteolin-mediated Kv1.3 K+ channel inhibition augments BCG vaccine efficacy against tuberculosis by promoting central memory T cell responses in mice

Despite the availability of multiple antibiotics, tuberculosis (TB) remains a major health problem worldwide, with one third of the population latently infected and similar to 2 million deaths annually. The only available vaccine for TB, Bacillus Calmette Guerin (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 (T-CM) cells, whereas effector memory T (T-EM) 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 T-EM but not T-CM cells, profoundly enhances T-CM cell differentiation. We exploited this phenomenon to improve T-CM:T-EM cell ratios and protective immunity againstMycobacterium tuberculosisinfection in response to BCG vaccination of mice. We demonstrate that luteolin, a plant-derived Kv1.3 K(+)channel inhibitor, profoundly promotes T-CM cells by selectively inhibiting T-EM 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. Author summary Bacillus Calmette Guerin (BCG) is not effective against adult pulmonary tuberculosis (TB). Inhibition of the Kv1.3 K+ ion channel by the antibiotic clofazimine has been shown to enhance BCG-induced immunity. However, clofazimine has limited efficacy and is associated with substantial side effects in treated patients. Therefore, we explored alternatives to clofazimine. Luteolin is a plant-based flavonoid that inhibits Kv1.3. We show that administration of luteolin during BCG vaccination enhances antigen-specific immunity by promoting the T central memory (T-CM) cell pool, which is critically important for long term host protection. Consequently, luteolin-mediated immune modulation enhances vaccine efficacy. As luteolin is a biologically safe food supplement, it could be easily applied during vaccination.