Tissue-specific transcriptional profiling of plasmacytoid dendritic cells reveals a hyperactivated state in chronic SIV infection

Abstract

HIV associated immune activation (IA) is associated with increased morbidity in people living with HIV (PLWH) on antiretroviral therapy, and remains a barrier for strategies aimed at reducing the HIV reservoir. The underlying mechanisms of IA have not been definitively elucidated, however, persistent production of Type I IFNs and expression of ISGs is considered to be one of the primary factors. Plasmacytoid DCs (pDCs) are a major producer of Type I IFN during viral infections, and are highly immunomodulatory in acute HIV and SIV infection, however their role in chronic HIV/SIV infection has not been firmly established. Here, we performed a detailed transcriptomic characterization of pDCs in chronic SIV infection in rhesus macaques, and in sooty mangabeys, a natural host non-human primate (NHP) species that undergoes non-pathogenic SIV infection. We also investigated the immunostimulatory capacity of lymph node homing pDCs in chronic SIV infection by contrasting gene expression of pDCs isolated from lymph nodes with those from blood. We observed that pDCs in LNs, but not blood, produced high levels of IFNα transcripts, and upregulated gene expression programs consistent with T cell activation and exhaustion. We apply a novel strategy to catalogue uncharacterized surface molecules on pDCs, and identified the lymphoid exhaustion markers TIGIT and LAIR1 as highly expressed in SIV infection. pDCs from SIV-infected sooty mangabeys lacked the activation profile of ISG signatures observed in infected macaques. These data demonstrate that pDCs are a primary producer of Type I IFN in chronic SIV infection. Further, this study demonstrated that pDCs trafficking to LNs persist in a highly activated state well into chronic infection. Collectively, these data identify pDCs as a highly immunomodulatory cell population in chronic SIV infection, and a putative therapeutic target to reduce immune activation.

Metabolic Deficiencies Underlie Plasmacytoid Dendritic Cell Exhaustion After Viral Infection

“…Through our analysis we generated the first gene signature of pDC exhaustion. Notably, this independently identified several known regulators of pDC IFN-I production ( Cd81 45,46 , Myc 47 ) as well as several genes with unknown relationship to pDC function, but previously identified as differentially expressed in pDC from SIV-infected macaques ( Tigit ) 44 . Tigit is of particular interest since it is a surface expressed protein and a known regulator of exhaustion in CD8 T cells and being explored as a target in cancer immunotherapy 98 .…”

“…Altogether this identified 36 genes that met these criteria. This “pDC exhaustion signature”, includes several notable genes that have previously been observed to be altered in exhausted pDCs during SIV infection ( Tigit, Ccr5 ) 44 , as well as molecules known to regulate pDC function ( Cd81 45,46 , Myc 47 ) (Fig. 1e).…”

Model for predicting age-dependent safety and immunomodulatory effects of STING ligands in non-human primates

“…In this study, we analyzed immune parameters mostly from cells in the blood but not at the injection site, where the STING-L concentration is likely to be the highest. As pDC is known to be activated in tissues, 60 , 61 the immune profiling of tissues would give a different perspective. In this study, we did not show vehicle-only treatment controls due to the limitation of available monkeys.…”

The role of plasmacytoid dendritic cells (pDCs) in immunity during viral infections and beyond

“…pDCs were also shown to be a major source of IFNs during the acute phase of systemic infection of macaques with simian immunodeficiency virus (SIV) (Table 3) [98]. The contribution of pDCs to IFN production during the chronic phase of SIV infection is controversial, with a lack of detection by intracellular staining of cells isolated from lymph node biopsies in one study [98] versus specific detection of IFN transcripts in pooled pDCs isolated from the lymph nodes at necropsy in another study [125]. This Minor [114] Spleen homogenate [110], lung homogenate [109,112], lung [111,113,115,116]; BAL [111,114]; ELISA, qRT-PCR [111,113,115,116] Controversial Putatively protective role, Bst2 + cell depletion increased viral titers in Mx1 + C57BL/6 mice [117] Putatively deleterious role, Bst2 + cell depletion slightly decreased viral titers in Mx1 -/-BALB/c mice [112,115] and reduced their morbidity and mortality [115]; Bst2 + cell depletion reduced the morbidity and mortality of 129S mice [111,116] Redundant role, lack of pDCs in Ikaros L/L or anti-Bst2-treated mice did not change viral titers and survival [110,114] Putatively contributes to innate immunity and inflammation, with contrasting results in anti-Bst2-treated mice: higher numbers of monocytes and production of TNF and IL-6 [112] versus reduced numbers of monocytes and production of inflammatory cytokines [111,116] Putatively contributes to modulate adaptive immunity: reduction of anti-IAV antibodies in anti-Bst2-treated C57BL/6 [114] controversy illustrates a possible sensitivity threshold issue, whereby it might be technically difficult to detect IFN-producing pDCs when their frequency is very low and a limited number of cells are analyzed.…”