MR1‐dependent immune surveillance of the skin contributes to pathogenesis and is a photobiological target of UV light therapy in a mouse model of atopic dermatitis

Abstract

Background: Mucosal-associated invariant T (MAIT) cells are unconventional T cells which recognize microbial metabolites presented by the major histocompatibility complex class I-related molecule MR1. Although MAIT cells have been shown to reside in human and murine skin, their contribution to atopic dermatitis (AD), an inflammatory skin disease associated with barrier dysfunction and microbial translocation,has not yet been determined.Methods: Genetic deletion of MR1 and topical treatment with inhibitory MR1 ligands, which result in the absence and functional inhibition of MAIT cells, respectively, were used to investigate the role of MR1-dependent immune surveillance in a MC903driven murine model of AD. Results:The absence or inhibition of MR1 arrested AD disease progression through the blockade of both eosinophil activation and recruitment of IL-4-and IL-13producing cells. In addition, the therapeutic efficacy of phototherapy against MC903driven AD could be increased with prior application of folate, which photodegrades into the inhibitory MR1 ligand 6-formylpterin. Conclusion:We identified MAIT cells as sentinels and mediators of cutaneous type 2 immunity. Their pathogenic activity can be inhibited by topical application or endogenous generation, via phototherapy, of inhibitory MR1 ligands.

Goat Milk–Derived Lipids Restrain NK T Cell–Dependent Eosinophilic Inflammation in a Murine Model of Atopic Dermatitis

“…Since the role of NKT cells in the context of AD remains to be elucidated, we sought to provide a tentative mechanism whereby NKT cells contribute to disease progressiona mechanism which could ultimately be modulated through dietary lipids. We previously reported the eosinophil-dependence of MC903-driven AD (Naidoo et al, 2018) and, using the same model, have more recently described the function of MAIT cells as cellular checkpoints for eosinophil activation in situ (Naidoo et al, 2021). As we comparatively quantified eosinophilia in WT, MR1 -/and CD1 -/ears, it became apparent that the significant reductions in ear thickness (Figure 1b) and TEWL (Figure 1c) observed in MR1 -/and CD1 -/-J o u r n a l P r e -p r o o f mice reflected distinct mechanistic pathways.…”

“…To determine if the consumption of GM infant formula (GMF) can decrease AD disease severity, we used a previously described MC903-driven model of AD-like disease (Li et al, 2009, Li et al, 2006, Naidoo et al, 2018, Naidoo et al, 2021. All strains of mice were housed under specific pathogen free (SPF) condition at the Malaghan Institute of Medical Research.…”

“…Thus, both wild-type (WT) C57Bl/6 and NKT cell-deficient CD1(d) -/mice were supplemented daily with GMF for a week prior, and during the 19 day-long MC903 AD model (Figure 1a). Mucosal-associated invariant T (MAIT) cell-deficient MR1 -/mice served as positive controls for therapeutic activity, as recently described (Naidoo et al, 2021), as well as negative controls for the abrogation of any lipid-mediated disease reduction.…”

“…As we comparatively quantified eosinophilia in WT, MR1 -/and CD1 -/ears, it became apparent that the significant reductions in ear thickness (Figure 1b) and TEWL (Figure 1c) observed in MR1 -/and CD1 -/-J o u r n a l P r e -p r o o f mice reflected distinct mechanistic pathways. Indeed, while MAIT cells exclusively control eosinophil activation (Figures 1g, h and (Naidoo et al, 2021)), the recruitment of eosinophils seems in turn to largely rely upon NKT cells, in an eotaxin-independent manner (Figure 1i). Eosinophil recruitment was also responsive to dietary GM intervention, in a milk fat-dependent manner (Figure 1j).…”

“…Milk products (goat milk formula, GMF; whole goat milk powder, WMP; skim goat milk powder, SMP) were reconstituted in water at the concentration used for human consumption (14.6 g/100mL) and fed either via gavage or provided ad libitum, which yielded similar results. At the experimental endpoint, ear thickness, transepidermal water loss (TEWL) and eosinophil quantification by confocal microscopy and flow cytometry were performed as previously described(Naidoo et al, 2021). b Effect of GMF on ear thickness at day 19 of MC903 treatment.…”