Blockade of the Kv1.3 K+ Channel Enhances BCG Vaccine Efficacy by Expanding Central Memory T Lymphocytes

J Infect Dis. 2016 Nov 1;214(9):1456-1464. doi: 10.1093/infdis/jiw395. Epub 2016 Aug 28.

Abstract

Tuberculosis is the oldest known infectious disease, yet there is no effective vaccine against adult pulmonary tuberculosis. Emerging evidence indicates that T-helper 1 and T-helper 17 cells play important roles in host protection against tuberculosis. However, tuberculosis vaccine efficacy in mice is critically dependent on the balance between antigen-specific central memory T (Tcm) and effector memory T (Tem) cells. Specifically, a high Tcm/Tem cell ratio is essential for optimal vaccine efficacy. Here, we show that inhibition of Kv1.3, a potassium channel preferentially expressed by Tem cells, by Clofazimine selectively expands Tcm cells during BCG vaccination. Furthermore, mice that received clofazimine after BCG vaccination exhibited significantly enhanced resistance against tuberculosis. This superior activity against tuberculosis could be adoptively transferred to naive, syngeneic mice by CD4+ T cells. Therefore, clofazimine enhances Tcm cell expansion, which in turn provides improved vaccine efficacy. Thus, Kv1.3 blockade is a promising approach for enhancing the efficacy of the BCG vaccine in humans.

Keywords: BCG vaccine; Kv1.3 potassium ion channel; Memory T cells; Mycobacterium tuberculosis; clofazimine.

MeSH terms

  • Adjuvants, Immunologic / administration & dosage
  • Animals
  • BCG Vaccine / immunology*
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / immunology*
  • Clofazimine / therapeutic use
  • Immunologic Memory / drug effects*
  • Immunologic Memory / immunology*
  • Kv1.3 Potassium Channel / antagonists & inhibitors*
  • Mice
  • Mice, Inbred C57BL
  • Mycobacterium / immunology
  • Tuberculosis Vaccines / immunology*
  • Tuberculosis, Pulmonary / immunology
  • Vaccination / methods

Substances

  • Adjuvants, Immunologic
  • BCG Vaccine
  • Kv1.3 Potassium Channel
  • Tuberculosis Vaccines
  • Clofazimine