Monocytes, viruses and metaphors

Keywords: :

• dendritic cell
• macrophage
• monocyte
• T cell
• virus

This article refers to:

Beginning in 1973, Ralph Steinman, initially working with Zanvil Cohn, described and characterized immune dendritic cells (DCs) as potent stimulators of T-cell responses.¹ Nearly 40 years later, DCs have become a central topic of immunological research due to their protean participation in immunity, both as activators of naïve T cells and as sentinel cells whose cytokine products regulate the type and vigor of immune responses. The importance and clinical potential of DCs was recognized by Steinman’s sharing the 2012 Nobel Prize for Medicine and Physiology.

Despite intense interest in DCs, there are numerous lacunae in our knowledge, not the least regarding their participation in immunity to microbial pathogens. The role of DCs in activating virus-specific T cells, while stated as a simple fact in most immunology textbooks, rests on precious little direct experimental support. In vivo evidence for an essential role of DCs (as opposed to monocytes/macrophages or other antigen-presenting cells) in “direct priming” (i.e., presenting viral antigens synthesized following infection) for anti-viral immunity was only published this year in an intravital microscopy study from our laboratory.² Based simply on the number of publications, it might be erroneously assumed that most anti-viral T cells are activated by DCs “cross-presenting” antigens obtained from virus-infected cells. In fact, while there is little doubt (outside of Zurich anyway)³ that cross priming is a major contributor to T-cell activation, the relative contributions of cross- vs. direct-priming are uncertain and are likely to vary enormously depending on the precise conditions of infection (virus, antigen, dose and route of infection).⁴

The fact that DCs are readily infectable by many viruses is in itself an interesting phenomenon typically given little extra thought. From the virus’s point of view, DCs are easily accessed in peripheral or immune organs and, as migratory cells, provide free transportation to other potential target cells.⁵ There are multiple examples of viruses both complex and simple, with the ability to subvert DC/MP function to dampen or redirect immune responses.

At the same time, hosts are not just sitting ducks for viruses. This is clearly shown by our study recently published in Blood,⁶ which started when Wanqiu Hou, a post-doctoral fellow in our laboratory, asked a simple but largely unanswered question: what cells in human blood are infectable by a panel of model viruses? We found that lymphocytes are highly resistant to infection by influenza A, vaccinia and vesicular stomatitis viruses. This was a surprise, considering that these viruses are famously promiscuous in their use of receptors and bind to virtually any mammalian cell type. DCs and monocytes (abundant blood cells that typically differentiate into macrophages after emigrating into tissues), on the other hand, were highly infectable by each of these viruses.

So who is winning this skirmish? Do viruses evolve to infect DCs and monocytes but not lymphocytes, or is it the other way around? We argue for the latter possibility, based on Wanqiu’s remarkable observation. Although the viruses he studied are well known for their abilities to divert ribosomes to preferentially synthesize viral gene products at the expense of host gene expression and do, in fact, robustly synthesize viral proteins in monocytes, it was not enough to prevent the rapid differentiation of infected monocytes into cells with a DC phenotype (i.e., they express a number of DC marker proteins) concomitant with increased potency as antigen presenting cells. A more general role for monocytes/macrophages in co-opting viral gene expression is supported by the findings of Honke et al., who elegantly demonstrated that macrophages suppress type I interferon signaling to facilitate viral replication as a necessary event to mount an effective immune response.⁷

This suggests a model in which DC/MPs essentially lure viruses into revealing immunologic information in the cell types most able to make use of it. Metaphorically, DC/MPs provide viruses with just enough replicative rope to hang themselves with. This strategy is particularly well suited for dealing with viruses exploring new host territory. Viruses, being clever little beasts, when given enough evolutionary time, can turn the tables on the host, now creating Trojan horses out of infected DCs/macrophages, providing endless challenges (and metaphors) for viral immunologists in understanding this cat and mouse game.

Acknowledgments

The authors are supported by Division of Intramural Research, NIAID, Bethesda, MD