Dengue virus-infected dendritic cells, but not monocytes, activate natural killer cells through a contact-dependent mechanism involving adhesion molecules

Costa, V. V., et al. (2017). MBio 8(4). e00741-17

Speaker: Sen-Mao Tien (田森貿)                                          Time: 15:00~16:00, Jan. 17, 2018

Commentator: Dr. Bei-Chang Yang (楊倍昌 老師)            Place: Room 601

Abstract:

        Dengue virus (DENV) belonging to the genus Flavivirus, family Flaviviridae is an arbovirus, and could cause many symptoms including life-threatening dengue hemorrhagic fever. Natural killer (NK) cells play crucial roles in DENV infection; however, the mechanism of NK cell activation in DENV infection is still unclear. Although monocytes and macrophages have been considered as dominant targets infected by DENV, the resident dendritic cells (DCs) in skin may be the first cell type to be infected during the natural DENV infection after a mosquito bite. In this study, the authors used co-culture system of monocyte-derived dendritic cells (MDDCs) and human NK cells which were obtained from the same peripheral blood mononuclear cell (PBMC) sample to test whether DENV-infected MDDCs (iMDDCs) could activate NK cells. The in vitro results showed that NK cells can be activated by iMDDCs through cell-cell contact molecules, but not by DENV-infected monocytes (iMOs). To further understand the relationship between iMDDCs and NK cells, they blocked adhesion molecules (DNAM-1, 2β4, LFA-1 and CD2) on NK cells, and data showed that the absence of cell contact molecules would inhibit NK cell activation, IFN-γ secretion, and cause elevation of viral titers. Furthermore, the in vivo studies using NK-optimized humanized mice (humice) highlighted the importance of human NK cells. In summary from the in virto and in vivo humice studies, the authors identify adhesion molecules and delineate the sequence of events contributing to NK cell activation and protection from DENV infection.

References:

1.      Lim, D. S. L., et al. (2014). "The combination of type I IFN, TNF-α, and cell surface receptor engagement with dendritic cells enables NK cells to overcome immune evasion by dengue virus." J Immunol 193(10): 5065-5075

2.      Costa, V. V., et al. (2013). "Inflammatory and innate immune responses in dengue infection: protection versus disease induction." Am J Pathol 182(6): 1950-1961.