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The regulation and pharmacological modulation of immune complex induced type III IFN production by plasmacytoid dendritic cells [RNA-seq]

ABSTRACT: Objective: Patients with Systemic Lupus Erythematosus (SLE) have an ongoing interferon (IFN) production due to an activation of plasmacytoid dendritic cells (pDCs), which can be triggered to type I IFN synthesis by RNA containing immune complexes (RNA-IC). Considering emerging data suggesting a role of type III interferon (IFN) in the SLE disease process, we asked if RNA-IC can induce type III IFN production in pDC, and how this production can be regulated. Methods: Peripheral blood mononuclear cells (PBMCs) or immune cell subsets were isolated from healthy blood donors or SLE patients and stimulated with IC containing U1 snRNP and SLE-IgG (RNA-IC). Hydroxychloroquine (HCQ) and an interleukin receptor 1 associated kinase 4 inhibitor (IRAK4i) were added to cell cultures. Cytokine mRNA levels were determined with a microarray and protein levels with immunoassays. Single-cell RNA-sequencing of pDCs using ddSEQ technology was performed. Results: Type III IFN mRNA and protein was induced in RNA-IC stimulated pDC-NK and pDC-B cell co-cultures. A subset of activated pDCs (3%) expressed both type III and type I IFN mRNA. IFN-λ2, IFN-α2b, interleukin (IL)-3, IL-6 or granulocyte-macrophage colony stimulating factor (GM-CSF) enhanced IFN-λ1/3 production 2-5-fold. HCQ and an IRAK4i blocked the RNA-IC-triggered IFN-λ1/3 production (p<0.01). IFN-α2b and GM-CSF increased the proportion of SLE patients producing IFN-λ1/3 in response to RNA-IC from 11 to 33%. Conclusions: Type III IFN production is triggered by RNA-IC in pDCs in a TLR-MyD88-dependent manner, enhanced by NK and B cells as well as several pro-inflammatory cytokines. These results support a contributing role for both type I and type III IFNs in SLE, which needs to be considered when targeting the IFN system in this disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148902 | GEO | 2020/05/23

REPOSITORIES: GEO

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Project description:Type I interferon (IFN), namely IFN- α, and B cell aberrations are long recognized in systemic lupus erythematosus (SLE) pathogenesis. Type I IFN receptor blockade has undergone clinical trials in SLE with varying degrees of success. Type III IFN (IFN-λ) produce a gene signature currently indistinguishable from that of type I in responsive cell types. IFN-λ are not blocked by type I IFN receptor blockade as they utilize a unique receptor (IFNLR1). Type III IFN are appreciated to have an important role in viral infection at epithelial barriers where IFNLR1 is strongly expressed. The effects of IFN-λ on immune cells remain understudied and are different between human and murine models. We have previously shown that human B cells can transcribe type I IFN genes after IFN-λ treatment including those associated with SLE. We have found that IFN-λ is detected in the serum of human SLE patients and correlates with IgD- CD27- CD21- CD24- (DN2) B cells, a compartment which contains CD11c+ age/autoimmunity B cells (ABC). ABC are a target of interest as recent studies suggest they are poised for plasma cell differentiation and enriched in autoreactivity and thus have the potential to contribute to SLE pathogenesis. Results: Naïve and DN cells display a prominent type I IFN gene expression profile in SLE. Transcript for type I, type II, and type III IFN receptors (IFNAR1, IFNAR2, IFNGR1, IFNGR2, IFNLR1, and IL10RB) are detected in HD and SLE B cells. CD11c+ CD21- frequency increased in DN compared to naïve B cells for SLE and HD (both p< 0.001). The mean and range of CD11c+ CD21- frequency was higher in SLE DN (30.7± 9.5%, mean±SEM; range 4.8-74.7%) compared to HD DN (7.6%±1.0%,3.6-9.4%). Increased IFNLR1 transcript correlated with CD11c+ CD21- B cell expansion (r2=0.922, p<0.0001). Increased pSTAT1 after IFN-α2 treatment is found in monocytes, T cells, and B cells but only in the B cells after IFN-λ1 treatment. Naïve, DN, switched, and unswitched memory HD B cells are responsive to type I and type III IFN, but demonstrated a higher pSTAT1 fold change with type I IFN treatment compared to type III IFN. In all B cell subsets, CD11c+ cells had a higher pSTAT1 fold change after IFN-λ1 stimulation than did CD11c- B cells. In HD with well-defined populations of CD11c+ CD21- DN cells, pSTAT1 fold change for IFN-λ approached that of IFN-α2. Conclusions: All human B cell subsets defined by CD27 and IgD respond to IFN-α and IFN-λ, but those expressing CD11c+ have increased responsiveness to IFN-λ. CD11c+ cells expand in SLE and associate with autoreactive plasma cell development. Thus, the role of IFN-λ may take on increased clinical significance in the setting type I IFN receptor blockade. These results suggest IFN-λ is an underappreciated driver of the IFN signature and B cell aberrations in SLE.

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The regulation and pharmacological modulation of immune complex induced type III IFN production by plasmacytoid dendritic cells [RNA-seq]

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