MyD88-Mediated Instructive Signals in Dendritic Cells Regulate Pulmonary Immune Responses during Respiratory Virus Infection

Abstract

Respiratory syncytial virus (RSV) is the leading cause of respiratory disease in infants worldwide. The induction of innate immunity and the establishment of adaptive immune responses are influenced by the recognition of pathogen-associated molecular patterns by TLRs. One of the primary pathways for TLR activation is by MyD88 adapter protein signaling. The present studies indicate that MyD88 deficiency profoundly impacts the pulmonary environment in RSV-infected mice characterized by the accumulation of eosinophils and augmented mucus production. Although there was little difference in CD4 T cell accumulation, there was also a significant decrease in conventional dendritic cells recruitment to the lungs of MyD88−/− mice. The exacerbation of RSV pathophysiology in MyD88−/− mice was associated with an enhanced Th2 cytokine profile that contributed to an inappropriate immune response. Furthermore, bone marrow-derived dendritic cells (BMDC) isolated from MyD88−/− mice were incapable of producing two important Th1 instructive signals, IL-12 and delta-like4, upon RSV infection. Although MyD88−/− BMDCs infected with RSV did up-regulate costimulatory molecules, they did not up-regulate class II as efficiently and stimulated less IFN-γ from CD4+ T cells in vitro compared with wild-type BMDCs. Finally, adoptive transfer of C57BL/6 BMDCs into MyD88−/− mice reconstituted Th1 immune responses in vivo, whereas transfer of MyD88−/− BMDCs into wild-type mice skewed the RSV responses toward a Th2 phenotype. Taken together, our data indicate that MyD88-mediated pathways are essential for the least pathogenic responses to this viral pathogen through the regulation of important Th1-associated instructive signals.

A Respiratory Syncytial Virus (RSV) Anti-G Protein F(ab′)2Monoclonal Antibody Suppresses Mucous Production and Breathing Effort in RSV rA2-line19F-Infected BALB/c Mice

“…Production of IL-12 is thought to favor differentiation and function of (Th1) T cells while inhibiting the differentiation of Th2 cells. In many viral infections, IL-12 promotes viral clearance and host recovery from infection (71)(72)(73)(74).…”

Respiratory Syncytial Virus Activates Innate Immunity through Toll-Like Receptor 2

“…Interestingly, the type of inflammatory environment generated during these early signaling events likely alters subsequent T-cell responses, because susceptible infants exhibit characteristics of Th2 responses (6). Since recent findings have implicated TLR-mediated inflammation in the immunopathogenesis of RSV disease, emphasis has been placed on understanding how TLRs can influence immune responses against RSV (3,7,28,36,39,50).…”

“…We observed a decrease in activated lung DCs (CD11b hi CD11c hi CD86 ϩ ) in TLR2 KO mice at 24 and 48 h postinfection, suggesting that TLR2-mediated signals generated during RSV infection could influence DC activation. Interestingly, Rudd et al showed that a lack of MyD88-dependent signaling in DCs can promote Th2 responses after RSV infection (39). Additionally, TLR2 signaling may further contribute to RSV responses by facilitating interactions between DCs and neutrophils that can further shape T-and B-cell polarization (34).…”

How are TH1 and TH2 effector cells made?

“…2) [18][19][20][21][22][23]. Furthermore, when overexpressed on APC or when crosslinked as fusion proteins, DLL ligands promote T H 1 cell differentiation [18,20,22,[24][25][26].…”