Filaggrin insufficiency renders keratinocyte-derived small extracellular vesicles capable of modulating CD1a-mediated T cell responses

Abstract

The promoting effect of FLG loss-of-function mutations on the development of atopic dermatitis (AD) signifies the role of filaggrin in the formation of a protective skin barrier; FLG mutations are also linked to asthma, food allergy and allergic rhinitis despite the absence of the protein in the affected tissues (lungs, intestines, and the majority of the nasal mucosa). AD patients suffer from chronic inflammation and recurrent skin infections; inflammation often precedes the appearance of spatially distant allergic manifestations. Here we show that exosome-enriched small extracellular vesicles (sEVs) secreted by filaggrin-knockdown keratinocytes are extensively remodelled as a consequence of the abnormal keratinocyte differentiation process. This alteration modulates the sEV capacity to promote type 1 and type 2 CD1a-dependent T cell responses by direct effects on self-lipid neoantigen generation; both modulating the amount of permissive (stimulatory) and non-permissive (inhibitory) CD1a ligands released from the sEV membranes by phospholipase A2. We found that this aberrant sEV lipid composition reflects a generalised cellular lipid bias with downregulation of multiple enzymes of lipid metabolic pathways, observed both in filaggrin knockdown keratinocytes in vitro, and in the skin of AD patients. Provision of modulatory ligands by sEVs secreted on a filaggrin insufficiency background, impeding both homeostatic autoreactive and protective antimicrobial CD1a-mediated type 1 and enhancing type 2 T cell responses provides basis for reduced tissue integrity and pathogen clearance and perpetuates inflammation in AD skin as well as in distant tissues to which sEVs are transferred by systemic circulation.

Excess filaggrin in keratinocytes is removed by extracellular vesicles to prevent premature death and this mechanism can be hijacked by Staphylococcus aureus in a TLR2‐dependent fashion

“…As for the lipid‐specific T cells, filaggrin has been documented to exert direct inhibitory action on the lipid neoantigen‐generating phospholipase A2 (PLA2) enzyme (Jarrett et al., 2016 ). Adding to that, we have very recently determined that sEV membranes themselves contain lipid antigens suitable for CD1a presentation and are capable of inducing protective and homeostatic T cell responses (Kobiela et al., 2022 ). However, filaggrin insufficient keratinocytes secrete sEVs characterised by altered lipidome which results in a bias of the CD1a‐dependent T cell responses from IFNγ‐dependent into type 2 inflammation with increased IL‐13 secretion, thus contributing to allergic inflammation.…”