Human blood CD14+ monocytes are bone marrow–derived white blood cells that sense and respond to pathogens. Although innate immune activation by RNA viruses preferentially occurs through intracellular RIG-I–like receptors, other nucleic acid recognition receptors, such as Toll-like receptors (TLRs), play a role in finely programming the final outcome of virus infection. Here, we dissected how human monocytes respond to infection with either Coxsackie (CV), encephalomyocarditis (EMCV), influenza A (IAV), measles (MV), Sendai (SV), or vesicular stomatitis (VSV) virus. We found that in monocytes, type I interferon (IFN) and cytokine responses to infection were RNA virus specific and differentially involved TLR7 and TLR8, which sense single-stranded RNA. These TLRs activated distinct signaling cascades in monocytes, which correlated with differences in the production of cytokines involved in the polarization of CD4+ T helper cells. Furthermore, we found that TLR7 signaling specifically increased expression of the transcription factor FOSL1, which reduced IL-27 and TNFα production by monocytes. TLR7, but not TLR8, activation of monocytes also stimulated Ca2+ flux that prevented type I IFN responses. Our work demonstrates that in human monocytes, TLR7 and TLR8 triggered different signaling pathways that contribute to distinct phenotypes during RNA virus infection. In addition, we defined individual targets within these pathways that promoted specific T helper and antiviral responses.

Pattern recognition of microbes by Toll-like receptors (TLR) is critical for innate immune system activation. Although TLRs are expressed in human CD4+ T cells, their function is not well understood. Here we demonstrate that engaging TLR7 in CD4+ T cells induces intracellular calcium flux with activation of an NFATc2-dependent anergic gene expression program and T cell non-responsiveness. As chronic infections with RNA viruses such as HIV-1 induce profound CD4+ T cell dysfunction, we examined the role of TLR7-induced anergy in HIV-1 infection. TLR7 gene silencing markedly decreases the frequency of HIV-1-infected CD4+ T cells and restores cell responsiveness in those HIV-1+ CD4+ T cells. These results elucidate a previously unknown function for microbial pattern recognition receptors to down-regulate immune responses.