Abstract
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.
Highlights
Despite the availability of multiple effective antibiotics, tuberculosis (TB) has emerged as the greatest killer among all infectious diseases, with one third of the global population infected, and 10.4 million new cases and ~1.74 million deaths reported in 2016 [1]
We show that administration of luteolin during Bacillus Calmette Guerin (BCG) vaccination enhances antigen-specific immunity by promoting the T central memory (TCM) cell pool, which is critically important for long term host protection
Our results demonstrate that mice receiving luteolin during BCG vaccination exhibit superior host protection against TB, which was associated with potent Th1 and Th17 responses, and enrichment of CD44hiCD62Lhi and CD44hiCCR7hi TCM cells in both CD4+ and CD8+ compartments
Summary
Despite the availability of multiple effective antibiotics, tuberculosis (TB) has emerged as the greatest killer among all infectious diseases, with one third of the global population infected, and 10.4 million new cases and ~1.74 million deaths reported in 2016 [1]. BCG elicits sufficient host protective T helper (Th) 1 (producers of IFN-γ) responses and exhibits efficacy against disseminated and meningeal TB in neonates. These cells become gradually exhausted and the host becomes again susceptible to Mycobacterium tuberculosis (M.tb) infection [3,4,5]. During the course of an ongoing infection, a wider pool of TCM cells is desired to provide the host with a continuous supply of TEM cells. The generation of TEM cells is proportionate to bacterial burden and these cells rapidly produce copious amounts of IFN-γ, which promotes cellular immune responses and eliminates bacteria. Increasing the pool of TCM (CD44hiCD62Lhi or CD44hiCCR7hi) cells by concomitant regulation of TEM (CD44hiCD62Llo or CD44hiCCR7lo) cells may be an effective strategy to develop long-lasting and robust recall responses
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