Plasmacytoid dendritic cells control T-cell response to chronic viral infection

Abstract

Infections with persistent viruses are a frequent cause of immunosuppression, autoimmune sequelae, and/or neoplastic disease. Plasmacytoid dendritic cells (pDCs) are innate immune cells that produce type I interferon (IFN-I) and other cytokines in response to virus-derived nucleic acids. Persistent viruses often cause depletion or functional impairment of pDCs, but the role of pDCs in the control of these viruses remains unclear. We used conditional targeting of pDC-specific transcription factor E2-2 to generate mice that constitutively lack pDCs in peripheral lymphoid organs and tissues. The profound impact of pDC deficiency on innate antiviral responses was revealed by the failure to control acute infection with the cytopathic mouse hepatitis virus. Furthermore, pDC-deficient animals failed to clear lymphocytic choriomeningitis virus (LCMV) from hematopoietic organs during persistent LCMV infection. This failure was associated with reduced numbers and functionality of LCMVspecific CD4 + helper T cells and impaired antiviral CD8 + T-cell responses. Adoptive transfer of LCMV-specific T cells revealed that both CD4 + and CD8 + T cells required IFN-I for expansion, but only CD4 + T cells required the presence of pDCs. In contrast, mice with pDC-specific loss of MHC class II expression supported normal CD4 + T-cell response to LCMV. These data suggest that pDCs facilitate CD4 + helper T-cell responses to persistent viruses independently of direct antigen presentation. Thus pDCs provide an essential link between innate and adaptive immunity to chronic viral infection, likely through the secretion of IFN-I and other cytokines.

Langerin neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

“…To test this hypothesis, we took advantage of two different pDC-deficient transgenic mouse strains. For one, DC-E2-2 −/− mice, in which the basic helix-loop-helix transcription factor (E protein) E2-2, essential for pDC development, is deleted in CD11c + cells, constitutively lack pDCs, whereas the cDC lineage is not affected (20). Second, hBDCA-2 DTR mice, that express the high-affinity diphtheria toxin receptor (DTR) under control of the human pDC-specific promoter blood dendritic cell antigen (BDCA)-2, enable efficient inducible pDC depletion by administration of DT (21).…”

Dendritic Cells Are Dispensable for T Cell Priming and Control of Acute Lymphocytic Choriomeningitis Virus Infection

“…Although it is well established that DCs can efficiently induce T cell immunity to LCMV, it remains unclear whether DCs are indeed required for T cell priming, acquisition of effector functions, and establishment of memory T cell populations. It was previously shown that selective and constitutive ablation of pDCs had no impact on CD4 and CD8 responses to acute LCMV infection but led to an impaired CD8 response to high-dose infection with the persistent LCMV strain Docile arguing for a critical role of pDCs as IFN producers to control persistent infections (21). Others have shown that cDCs are the main producers of IFN-I in response to acute LCMV infection, and cDC-derived IFN was required to mediate a CTL response to LCMV (19).…”

Conventional but Not Plasmacytoid Dendritic Cells Foster the Systemic Virus–Induced Type I IFN Response Needed for Efficient CD8 T Cell Priming

“…Moreover, Ikaros L/L mice, which lack peripheral pDCs but harbor normal numbers of cDCs, mount efficient B cell-and T cell-specific responses against the influenza virus (18). Other studies have shown that conditional deletion or Ab-mediated depletion of pDCs does not alter the induction of an antiviral CTL response (13,19).…”