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Review
. 2011 Oct;90(4):691-701.
doi: 10.1189/jlb.0311166. Epub 2011 Aug 15.

TLR7/9 versus TLR3/MDA5 signaling during virus infections and diabetes

Melissa Swiecki  1 , Stephen A McCartney, Yaming Wang, Marco Colonna
Affiliations
Review

TLR7/9 versus TLR3/MDA5 signaling during virus infections and diabetes

Melissa Swiecki et al. J Leukoc Biol. 2011 Oct.

Abstract

IFN-I are pleiotropic cytokines that impact innate and adaptive immune responses. In this article, we discuss TLR7/9 versus TLR3/MDA5 signaling in antiviral responses and diabetes. pDCs are thought to have a critical role in antiviral defense because of their ability to rapidly secrete large amounts of IFN-I through TLR7/9 signaling. A recent study demonstrates that although pDCs are a source of IFN-I in vivo, their overall contribution to viral containment is limited and time-dependent, such that additional cellular sources of IFN-I are required to fully control viral infections. dsRNA sensors, such as TLR3 and MDA5, provide another important trigger for antiviral IFN-I responses, which can be exploited to enhance immune responses to vaccines. In the absence of infection, IFN-I production by pDCs or from signaling through dsRNA sensors has been implicated in the pathogenesis of autoimmune diseases such as diabetes. However, recent data demonstrate that IFN-I production via TLR3 and MDA5 is critical to counter diabetes caused by a virus with preferential tropism for pancreatic β-cells. This highlights the complexity of the host antiviral response and how multiple cellular and molecular components balance protective versus pathological responses.

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Figures

Figure 1.
Figure 1.. Cellular sources of IFN-I during viral infections.
pDCs detect RNA and DNA viruses through endosomal TLR7 and TLR9, respectively, leading to the secretion of IFN-I. IFN-I production by pDCs is early and transient, suggesting a need for additional cellular sources that provide a more broad, extended production of IFN-I to resolve viral infections. Other cellular sources that are critical in the production or responsive to IFN-I during virus infections include monocytes, B cells, DCs, macrophages, and stromal cells, which can produce IFN-I via TLRs (TLR2, TLR3, TLR7, TLR9) and RLRs (RIG-I, MDA5, and LGP2), and cytoplasmic DNA sensors, which are not discussed in this review (DNA-dependent activator of IRFs; IFN-γ-inducible protein IFI16 or p204; stimulator of IFN genes; HMGB1 and HMGB2; DHX36) [–86]. Cytoplasmic helicases (DDX1-DDX21-DHX36 complex) have been identified, which sense dsRNA and activate IFN-I responses in the cytosol of myeloid DCs [87]. Macrophage subsets include subcapsular sinus macrophages, splenic marginal zone macrophages, metallophilic macrophages, microglia, and tissue macrophages, such as those found in the liver and lung (i.e., Kupffer and alveolar).
Figure 2.
Figure 2.. Poly(I:C) promotes T cell responses and NK cell activation through TLR3 and MDA5 signaling.
(A) TLR3 and MDA5 impact CD8+ and CD4+ T cell responses. Poly(I:C)-mediated stimulation of TLR3 is required in hematopoietic cells to promote cross-priming of antigen-specific CD8+ T cells, i.e., primary responses, whereas poly(I:C)-mediated stimulation of MDA5 is required in stromal cells to induce a systemic rise in IFN-I secretion that promotes the survival of antigen-primed CD8+ T cells and the establishment of CD8+ T cell memory. IFN-I, from hematopoietic and stromal cells, is necessary for the adjuvant function of poly(I:C) to induce effective CD4+ Th1 immunity. (B) Roles of TLR3 and MDA5 in poly(I:C)-mediated NK cell activation. TLR3 contributes to NK cell activation by promoting IFN-I and IL-12 release by hematopoietic cells, whereas MDA5 activates NK cells indirectly, by promoting stromal cell release of IFN-I.
Figure 3.
Figure 3.. Roles of MDA5 and TLR3 in virus-induced diabetes.
MDA5 has a dominant role in protecting the heart against EMCV-D infection. TLR3-deficient mice develop diabetes as a result of hematopoietic cells, failing to mount an early IFN-I response that protects β-cells from virus-induced damage. The role of MDA5 in virus-induced diabetes could not be assessed, as MDA5-deficient mice die from myocarditis within the first 5 days of infection. However, studies in MDA5+/− mice, which survive EMCV-D infection, do develop transient hyperglycemia, suggesting at least a partial for MDA5 in preventing virus-induced diabetes. Thus, IFN-I responses mediated by MDA5 and TLR3 can reduce viral replication, preventing β-cell destruction and diabetes.
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