Lactate Dehydrogenase-Elevating Virus Induces Systemic Lymphocyte Activation via TLR7-Dependent IFNα Responses by Plasmacytoid Dendritic Cells

Abstract

BackgroundLactate dehydrogenase-elevating virus (LDV) is a natural infectious agent of mice. Like several other viruses, LDV causes widespread and very rapid but transient activation of both B cells and T cells in lymphoid tissues and the blood. The mechanism of this activation has not been fully described and is the focus of the current studies.Principal FindingsA known inducer of early lymphocyte activation is IFNα, a cytokine strongly induced by LDV infection. Neutralization of IFNα in the plasma from infected mice ablated its ability to activate lymphocytes in vitro. Since the primary source of virus-induced IFNα in vivo is often plasmacytoid dendritic cells (pDC's), we depleted these cells prior to LDV infection and tested for lymphocyte activation. Depletion of pDC's in vivo eradicated both the LDV-induced IFNα response and lymphocyte activation. A primary receptor in pDC's for single stranded RNA viruses such as LDV is the toll-like receptor 7 (TLR7) pattern recognition receptor. Infection of TLR7-knockout mice revealed that both the IFNα response and lymphocyte activation were dependent on TLR7 signaling in vivo. Interestingly, virus levels in both TLR7 knockout mice and pDC-depleted mice were indistinguishable from controls indicating that LDV is largely resistant to the systemic IFNα response.ConclusionResults indicate that LDV-induced activation of lymphocytes is due to recognition of LDV nucleic acid by TLR7 pattern recognition receptors in pDC's that respond with a lymphocyte-inducing IFNα response.

Tetherin Promotes the Innate and Adaptive Cell–Mediated Immune Response against Retrovirus Infection In Vivo

“…As mentioned earlier, these experiments required LDV+ FV. LDV could potently stimulate IFNα production (38), and removal of LDV in the FV/LDV stocks reduced IFNα upregulation at 18 to 24 h post-infection (38, 39). Since Type I IFNs could significantly induce Tetherin expression (27, 40), it is possible that LDV co-infection may have primed the host to express unusually high levels of Tetherin (38, 39).…”

“…Thus, the relatively weak association between Tetherin and T cell responses in the B 1 experiments led us to perform a second set of studies, this time with B6 WT and B6 Tetherin KO mice at 14 dpi. Since LDV co-infection could alter adaptive immune responses to FV (15, 29, 38, 39, 58), and the experimental design was not constrained by genetic parameters defined by classical FV infection studies (in contrast to the B 1 study), we utilized LDV-free FV stocks. Further strengthening the role of Tetherin as an antiretroviral factor in vivo , we observed significantly higher FV infection levels in Tetherin KO mice.…”

Complement Opsonization Enhances Friend Virus Infection of B Cells and Thereby Amplifies the Virus-Specific CD8 + T Cell Response

“…Previous studies have shown that lactate dehydrogenaseelevating virus (LDV) infection caused a polyclonal activation of CD19 ϩ B cells, characterized by the expression of the early activation marker CD69 in vivo (1). With the aim of studying mined by fluorescence-activated cell sorting (FACS) using FV glyco-Gag-specific monoclonal antibody clone 34 as described elsewhere (4).…”

Plasmacytoid dendritic cells promote rotavirus-induced human and murine B cell responses

“…The resulting type I IFN response affects viral replication while simultaneously activating diverse immune effector cells (10). Specific ablation of pDCs during viral infection significantly diminishes the early type I IFN response (11)(12)(13)(14). During herpes simplex-1 and vesicular stomatitis virus infection, pDC depletion impairs CD8 + T cell immunity (12,15); similarly, during murine cytomegalovirus infection, the absence of pDCs results in diminished activation of early, nonspecific NK cells (12).…”