Interleukin-15 priming generates unique myeloid cells secreting interferon-gamma during differentiation of dendritic cells : immunotherapeutic implications in the control of tuberculosis

Abstract

Tuberculosis (TB) remains a global public threat, and its causative agent Mycobacterium tuberculosis (M. tuberculosis), has infected approximately one-third of the world’s population. Although Mycobacterium bovis, Bacille Calmette-Guerin (BCG), known as the only currently available vaccine, has shown its limitation, the efficacy of candidates has not been qualified yet. In this study, I focused on the thing that the cell therapies based on dendritic cells (DCs) have been reported to be useful against several diseases, such as cancer and infectious diseases including TB. Moreover, DCs characters depend on the environment such as cytokine which they have been encountered during their proliferation. Interleukin-15 (IL-15) is widely believed to play crucial roles in developmental process and functions of natural killer (NK) cells and T cells, also this cytokine is known as the only cytokine which is able to proliferate bone marrow cells into DCs. Interestingly, a recent report shows that the rate of survival against M. tuberculosis infections is enhanced in IL-15 treated mice. The aim of this study is to find out characters of IL-15-primed cells and to observe its capacity of killing M. tuberculosis. First, the increased level of interferon-gamma (IFN-γ) was found in lipopolysaccharide (LPS) treated IL-15-primed cells. Further, they less expressed CD11c compared to conventional DCs (cDCs), which proved that IL-15-primed cells are somewhat different from cDCs. However, NK cells, T cells and interferon-producing killer dendritic cells (IKDCs) also have similar characters and all of them are associated with IL-15. To distinct IL-15-primed cells from NK cells, T cells and IKDCs, enzyme-linked immunosorbent assay (ELISA) and fluorescence-activated cell sorting (FACS) analysis were performed, and their phenotypes proved the differences between each population mentioned above. In addition, when IL-15-primed cells were gated on with the markers specific for IL-15-primed cells, CD11cintCD11bintB220+Gr-1int, the gated population showed increased IFN-γ expression. As suggested, M. tuberculosis infected macrophages cocultured with IL-15-priemd cells presented decreased colony-forming unit (CFU). Thus, IL-15-primed cells, which have unique characters distinct from cDCs, NK cells, T cells and IKDCs, could further improve for applying therapeutic way against TB.