trust but verify

Innate immune system detects the pathogen invasion and alerts adaptive immune system to its presence. However it is not always clear whether adaptive immune system should be alerted to the presence of any dose of pathogenic inoculum. May be innate immune system can handle low dose of pathogenic inoculum alone? However, what if innate immune system tries to handle the pathogen alone, fails doing it and alerts adaptive immune system too late when pathogenic onoculum become too large? The exact balance that will increase protective immunity and at the same time reduce tissue damage will depend on many variables, many of them still unknown.

If you are interested to know more about the complex interaction between innate and adaptive immune systems, I will recommend reading the following research article published in Nature Immunology a few weeks ago. In this study by Nadine Honke et al. (1), the authors first showed that in mice, intravenously injected (i.v.) vesicular stomatitis virus (VSV) is rapidly captured and cleared from the bloodstream by tissue macrophages. However, interestingly, the authors could detect the presence of live virus only in spleen tissue. Specifically, live virus was maintained in specialized macrophages called marginal zone macrophage that are identified by staining for CD169 marker. In contract, live virus could be recovered from all tissue examined from wild-type mice depleted of macrophages or from mice deficient in IFN-α receptor. These results suggested that CD169+ macrophages have some unique properties that allow them to maintain live virus in wild-type mice. The authors showed it may be related to higher expression of IFN-α signaling inhibitor Usp18 in CD169+ macrophages as compared to other tissue macrophages, for example, F4/80+ macrophages. Indeed, expression of VSV was absent in CD169+ macrophages from Usp-18 deficient mice. In other words, CD169+ macrophages “intentionally” inhibit IFN-α signaling in order to maintain live virus. Why is that? The authors explained this puzzle by observation that VSV-specific T cell and IgG response were reduced in Usp-18 deficient mice. Moreover, Usp-18 deficient mice became very susceptible to i.v. Injected VSV. Usp-18 deficient mice harbor far less live virus in the spleen at early time point post infection (at 7h) and harbor far more live virus in brain at late time point post infection (at 7 days). In addition, the authors showed that live virus primed VSV-specific adaptive immune response more efficiently compared to inactivated VSV. The authors concluded that “deliberate” maintenance of replication-competent virus in CD169+ macrophages gives enough time or antigenic material for efficient priming of protective adaptive immune response, while inactive virus is far inferior in providing signals necessary for efficient priming of protective adaptive immune response.

However, there are several holes in the story. The authors did not show results whether (1) VSV-specific T cells response was reduced in mice depleted of CD169+ macrophages or (2) whether mice depleted of CD169+ macrophages became more susceptible to VSV. Without these controls the whole concept of the paper will be misleading.

David

1. http://www.nature.com/ni/journal/vaop/ncurrent/full/ni.2169.html