The innate immune system, that part of the immune system
that responds to non-specific signs of pathogen infection, faces a quandary
when mounting a response against a pathogen. On one hand, it must limit the replication
of the pathogen to prevent spread throughout the body. On the other, it must
facilitate the development of a specific adaptive immune response, which can
clear the pathogen from the body and lead to immunologic memory. It might seem
like both of these are reasonable tasks, but the quandary lies in the fact that
the adaptive immune system must be activated by a certain amount of antigen
(proteins derived from the pathogen that can be effectively targeted by the
immune system) in order to elicit an effective response. Low levels of antigen
lead to weak responses, whereas high amounts of antigen induce strong
responses. Thus, if the innate immune system does the first part of its job too
well and largely prevents virus replication, there will not be enough viral
antigen present to stimulate a robust adaptive response. So how does the immune
system get around this predicament? A new paper in Nature Immunology by Nadine Honke and her colleagues sheds some
light on this question (1).
The
major weapons in the innate immune system’s arsenal are small, secreted
proteins called interferons. When cells in the body detect a pathogen, they
produce interferons, which alert the surrounding cells to the impending danger.
These “warning flags” bind to interferon receptors found on the surface of all
cells, and induce the expression of a large number of genes, termed interferon
stimulated genes (ISGs), which can combat the pathogen through various means. Interferons
also initiate mechanisms that facilitate the adaptive immune response, by
increasing the presentation of specific antigens to the T cells and B cells
that comprise the adaptive immune system. To effectively stimulate T cells,
however, requires a sufficient dose of antigen: prior studies have indicated
that over 20,000 copies of the antigen are required for an antigen-presenting
cell to induce a robust T cell response (2). So, how can the innate immune
system effectively prevent the spread of a pathogen while still providing
enough “grist” to be presented to naïve T cells? Honke et al began to answer
this by examining a particular subset of innate immune cells, metallophilic
macrophages.
Macrophages
are phagocytic cells, which means that they engulf and digest pathogens and
cellular debris that they come into contact with. They play a role in both innate
immune processes, through their non-specific destruction of pathogens, and
adaptive immune processes, through their ability to activate T cells and B
cells. Metallophilic macrophages, a
subset of these cells also known as CD169+ macrophages, reside in
the lymph nodes and spleen, and filter the blood for antigens. This makes them
a good candidate for facilitating adaptive immune activation. Indeed, when the
authors depleted these macrophages from mice and then challenged them with
vesicular stomatitis virus (VSV), the virus remained in the blood stream for
longer periods than observed in normal mice, suggesting that these cells
efficiently filter the virus from the blood. The macrophage-depleted animals
also succumbed to the infection, unlike normal mice, indicating an important
role for macrophages in protecting the mice from lethal infection. The authors
examined virus replication in wild-type mice and mice that genetically lacked
the interferon receptor, and found that, as expected, in the absence of
interferon signaling, the virus replicated to high levels throughout the body.
In the wild-type mice, however, virus replication was only observed in the
spleen, the location of the CD169+ macrophages. When the authors
looked for the location of the virus antigen in the spleen, they found replicating
virus only in the CD169+ population (see figure). These results
suggest that this population of cells fosters virus replication, even in the
presence of effective interferon-mediated inhibition of infection in
neighboring cells and tissues.
So
how can CD169+ macrophages allow virus replication, despite the
antiviral effects of interferon? The answer lies in the cellular protein Usp18.
This protein is known to suppress interferon signaling (3), and Honke et al showed
that it was expressed at high levels in the CD169+ macrophages, but
not in other macrophage subsets. Mice that lacked Usp18 exhibited no VSV
antigen in the CD169+ population, and much lower titers of VSV in
the spleen. Thus, the metallophilic macrophages inure themselves to the
antiviral effects of interferon by expressing Usp18, in order to allow robust
virus replication!
The
next step was to link this phenomenon to the development of the adaptive immune
response. Honke et al found that the production of neutralizing antibodies by B
cells was significantly diminished following depletion of CD169+
macrophages, and both T cell and B cell responses were attenuated in mice
lacking Usp18. No differences were observed between wild-type and
Usp18-deficient mice when challenged with inactivated VSV, indicating that
replication-competent virus was necessary for this effect. These defects in
adaptive immune responses had consequences on the outcome of the infection, as
VSV was able to spread and cause a lethal central nervous system infection in
the Usp18-deficient animals.
To
summarize, interferons function to limit virus replication in most cells in the
body. CD169+ macrophages express Usp18 to suppress this response, allowing
for compartmentalized virus replication as a means of facilitating a large
enough antigen load to adequately prime the adaptive immune response. It
certainly seems counterintuitive to allow a virus to replicate at all when the
means of suppressing replication are readily available. Nevertheless, this
trade-off facilitates an even more effective adaptive immune response, and the
subsequent generation of immunologic memory. One outstanding question is
whether this subversion of the interferon response is complete, or just
targeted toward a handful of ISGs. Many ISGs are not directly anti-viral, but
function to increase antigen presentation, and so might not be beneficial to
inhibit even in the CD169+ macrophages. The subset of ISGs inhibited
by Usp18 expression in these cells remains to be elucidated.
Overall,
this manuscript has wide-ranging implications, especially for the development
of vaccines. It suggests that “live-attenuated” vaccines, which feature
replication-competent pathogens that have been neutered of their
disease-causing features, may be a far more efficient means of eliciting a
protective immune response than “inactivated” vaccines, which are
replication-incompetent. While this is certainly not a novel idea, this paper
reveals part of the mechanism behind this phenomenon and perhaps might allow
researchers to more efficiently target vaccines to the cell types, such as
CD169+ macrophages, that can elicit the most robust immune response.
(1)
Honke, N., et al. Enforced viral replication activates adaptive immunity and is essential for the control of a cytopathic virus. Nat. Immunol. 13, 51-57 (2012).
(2)
Henrickson, S.E. et al. T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation. Nat. Immunol. 9, 282–291 (2008).
(3)
Ritchie, K.J. et al. Role of ISG15 protease UBP43 (USP18) in innate immunity to viral infection. Nat. Med. 10, 1374–1378 (2004).
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