Antigen-Specific T-Cell Responses to a Recombinant Fowlpox Virus Are Dependent on MyD88 and Interleukin-18 and Independent of Toll-Like Receptor 7 (TLR7)- and TLR9-Mediated Innate Immune Recognition

Abstract

Fowlpox virus (FWPV) is a double-stranded DNA virus long used as a live-attenuated vaccine against poultry diseases, but more recent interest has focused on its use as a mammalian vaccine vector. Here, in a mouse model system using FWPV encoding the nominal target antigen chicken ovalbumin (OVA) (FWPV OVA ), we describe for the first time some of the fundamental processes by which FWPV engages both the innate and adaptive immune systems. We show that Toll-like receptor 7 (TLR7) and TLR9 are important for type I interferon secretion by dendritic cells, while TLR9 is solely required for proinflammatory cytokine secretion. Despite this functional role for TLR7 and TLR9 in vitro, only the adapter protein myeloid differentiation primary response gene 88 (MyD88) was shown to be essential for the formation of adaptive immunity to FWPV OVA in vivo. The dependence on MyD88 was confined only to the T-cell compartment and was not related to its contribution to TLR signaling, dendritic cell maturation, or the capture and presentation of FWPVderived OVA antigen. We demonstrate that this is not by means of mediating T-cell-dependent interleukin-1 (IL-1) signaling, but rather, we suggest that MyD88 functions to support T-cell-specific IL-18 receptor signaling, which in turn is essential for the formation of adaptive immunity to FWPV-encoded OVA.

Boosting Functional Avidity of CD8 + T Cells by Vaccinia Virus Vaccination Depends on Intrinsic T-Cell MyD88 Expression but Not the Inflammatory Milieu

“…6C). In agreement with previous reports (20,21,35), these data demonstrate that the inflammatory cytokines induced by VACV infection are decreased and that the ability to induce a CD8 ϩ T-cell response is retained in MyD88…”

“…The MyD88 pathway is vital for innate immunity to recognize VACV and to subsequently initiate adaptive immune responses (6,20,21). To test whether the MyD88 pathway is engaged in shaping the functional avidity of antigenspecific memory CD8 ϩ cells, we boosted MyD88 Ϫ/Ϫ mice with DNA vaccine or VACV vaccine and then determined the functional avidity of CD8 ϩ T cells (Fig.…”

“…Recent studies indicate that pathogen-specific inflammation provides the third signal that dy-namically tunes the functional avidity of CD8 ϩ T cells in combination with TCR ligation and costimulatory signaling stimulation (18,19). Interestingly, VACV could induce inflammatory cytokines through the MyD88-mediated pathway (20,21), and as such, MyD88-deficient mice display a diminished antigen-specific immune response to recombinant poxvirus-based vaccines (21). Accordingly, a series of clinical trials showed that the poxvirusbased vaccines are highly immunogenic in the context of vaccination regimen of DNA priming and poxvirus-vectored vaccine boost (7,22).…”

The plasmacytoid dendritic cell: at the cross-roads in asthma

“…In addition to TLR9, pDCs can also detect microbial DNA via the cytosolic helicase DHX36 (DExD/H-box helicase 36) which, like TLR9, employs the MyD88-IRF7 signal transduction cascade to induce IFN-I production [44]. Less is known about the expression of other PRRs, such as the NOD-like receptor family, although the ability to secrete mature IL-1b and IL-18 suggests that pDCs are capable of forming an active inflammasome [45][46][47]; further studies are warranted to investigate the nature of the inflammasome(s) in pDCs.…”

A West Nile virus NS4B-P38G mutant strain induces adaptive immunity via TLR7-MyD88-dependent and independent signaling pathways

“…Moreover, other cytokine receptor signaling pathways, such as those of IL-1R and IL-18R, which rely on MyD88 expression could be involved in memory T cell development. T cell responses during a recombinant fowlpox virus infection are mediated via the IL-18R-MyD88 signaling pathway [46]. Here, we found IL-1R signaling is involved in memory T cell response during secondary challenge with wild-type WNV.…”