Fc gamma receptor IIa suppresses type I and III interferon production by human myeloid immune cells

Abstract

Type I and type III interferons (IFNs) are fundamental for antiviral immunity, but prolonged expression is also detrimental to the host. Therefore, upon viral infection high levels of type I and III IFNs are followed by a strong and rapid decline. However, the mechanisms responsible for this suppression are still largely unknown. Here, we show that IgG opsonization of model viruses influenza and respiratory syncytial virus (RSV) strongly and selectively suppressed type I and III IFN production by various human antigen‐presenting cells. This suppression was induced by selective inhibition of TLR, RIG‐I‐like receptor, and STING‐dependent type I and III IFN gene transcription. Surprisingly, type I and III IFN suppression was mediated by Syk and PI3K independent inhibitory signaling via FcγRIIa, thereby identifying a novel non‐canonical FcγRIIa pathway in myeloid cells. Together, these results indicate that IgG opsonization of viruses functions as a novel negative feedback mechanism in humans, which may play a role in the selective suppression of type I and III IFN responses during the late‐phase of viral infections. In addition, activation of this pathway may be used as a tool to limit type I IFN‐associated pathology.

Dysregulated Fcγ receptor IIa-induced cytokine production in dendritic cells of lupus nephritis patients

“…To assess whether FcγR expression is different between HCs and SLE patients with or without nephritis, we determined FcγR mRNA expression on DCs of HCs and SLE patients. The main receptor that is responsible for the suppression of IFN‐β production by DCs is FcγRIIa , the expression levels of which were similar between the different groups (Fig. b).…”

“…Type I IFN responses are suppressed by the ‘inhibitory’ pathway, which is mediated by Syk‐ and PI3K‐independent signaling. Conversely, the ‘activating’ pathway signals through Syk and PI3K, which amplifies the production of proinflammatory cytokines such as IL‐1β . As our data demonstrate that in lupus nephritis patients the inhibitory pathway (that suppresses type I IFN) is impaired, we subsequently examined whether the activating pathway (that increases IL‐1β) is also impaired in lupus nephritis patients.…”

“…Previously, we identified that in healthy individuals IgG immune complexes strongly inhibit type I IFN production by DCs via inhibitory signaling through FcγRIIa . Because immune complexes consisting of IgG autoantibodies bound to autoantigens are continuously present in SLE patients, and SLE is strongly associated with increased levels of type I IFNs, in this study we investigated whether DCs of SLE patients display any abnormalities in FcγR‐induced suppression of type I IFN.…”

“…In this regard, it is important to realize that, specifically for type I IFN production (but not for other cytokines), FcγR stimulation has opposite effects on myeloid immune cells (such as conventional DCs, Langerhans cells, monocytes and macrophages) versus pDCs. While FcγRIIa stimulation suppresses PRR‐induced type I IFN (mainly IFN‐β) production by conventional DCs , FcγRIIa increases type I IFN (mainly IFN‐α) production by pDCs . We identified that specifically the inhibitory function of FcγRIIa on type I IFN production by myeloid DCs is impaired, which will lead to increased type I IFN production mainly in local tissues.…”

“…This suppression is induced by inhibitory signaling through Fcγ receptor IIa (FcγRIIa, or CD32a), a receptor that recognizes immunoglobulin (Ig)G immune complexes. The physiological function of inhibitory signaling by FcγRIIa in healthy individuals is to down‐regulate type I IFN responses during the late phase of viral infections, which is triggered by anti‐viral IgG antibodies that opsonize viruses and thereby form immune complexes .…”