CX3CR1 ⁺ mononuclear phagocytes control immunity to intestinal fungi

Abstract

Intestinal fungi are an important component of the microbiota, and recent studies have unveiled their potential in modulating host immune homeostasis and inflammatory disease. Nonetheless, the mechanisms governing immunity to gut mycobiota remain unknown. We identified CX3CR1+ mononuclear phagocytes (MNPs) as essential for the initiation of innate and adaptive immune responses to intestinal fungi. CX3CR1+ MNPs express antifungal receptors and activate antifungal responses in a Syk dependent manner. Genetic ablation of CX3CR1+ MNPs led to changes in the gut fungal communities and to severe colitis that was rescued by antifungal treatment. A missense mutation in the gene encoding CX3CR1 led to impaired antifungal responses in Crohn’s Disease patients. These results unravel the role of CX3CR1+ MNPs as mediators of the interactions between intestinal mycobiota and host immunity during health and disease.

Response to Fungal Dysbiosis by Gut-Resident CX3CR1+ Mononuclear Phagocytes Aggravates Allergic Airway Disease

“…However, the potential mechanisms through which immune cells recognize fungal dysbiosis-derived signals to regulate distal allergic airway immune responses remain poorly characterized. We have recently shown that CX3CR1 + MNPs that express several antifungal receptors can efficiently recognize and uptake gut commensal fungi (Cook and MacDonald, 2016; Leonardi et al, 2018). Therefore, we next hypothesized that the direct sensing of fungi by gut CX3CR1 + MNPs might be responsible for the distal effects of fungal dysbiosis on systemic immunity and lung airway inflammation.…”

“…Gut-resident CX3CR1 + MNPs play a critical role in regulation of intestinal immune response to bacteria and fungi under homeostatic and dysbiotic conditions (Diehl et al, 2013; Kim et al, 2018; Leonardi et al, 2018; Panea et al, 2015). Although fluconazole treatment contributed to increases of CD4 + T cell frequencies in the lung of HDM-immunized mice, we did not observe changes in CX3CR1 + MNPs frequencies in the lung of those mice (Figure 4A).…”

“…We therefore reasoned that CX3CR1 + MNPs local responses to fungi in the gut might be responsible for the observed phenotypes during fungal dysbiosis. CX3CR1 + MNPs express Syk that is crucial for the initiation of the signaling cascades downstream of anti-fungal C-type lectin receptors (CLRs) activation (Leonardi et al, 2018). We have previously shown that selective depletion of Syk in CX3CR1 + MNPs can be achieved by activating tamoxifen-inducible Cre recombinase in Syk fl/fl x Cx3cr1-Cre/ERT mice with tamoxifen (Leonardi et al, 2018).…”

“…The intestines harbor several subsets of phagocytes, which are known to respond to infections or to fluctuations in the commensal bacteria and fungi (Diehl et al, 2013; Leonardi et al, 2018; Mowat and Agace, 2014; Panea et al, 2015). We have recently shown that among these a population of CX3CR1 + gut resident mononuclear phagocytes (MNPs) expresses several antifungal receptors and is crucial for the induction of innate and adaptive immune responses to intestinal fungi (Leonardi et al, 2018). Whether fungal sensing in the gut can influence immunity at other body sites is currently unknown.…”

Antifungal Innate Immunity: A Perspective from the Last 10 Years

“…Furthermore, CX 3 CR1+ cells have been shown to directly transfer antigens to CD103+ DCs via gap junctions to induce tolerance [161]. A recent study has identified that CX 3 CR1+ mononuclear phagocytes are essential for the initiation of innate and adaptive immune responses to intestinal fungi in the colon and mesenteric lymph nodes but not the small intestine, and genetic ablation of CX 3 CR1+ cells in mice led to changes in gut fungal communities and the development of severe colitis [162]. …”