Despite its importance as the outer most barrier, our understanding of skin immunology lags behind that of the gut. Barrier disruption and percutaneous sensitization are major pathological processes in atopic dermatitis that lead to asthma and food allergy, and vaccination is most efficacious when delivered via skin. Thus, skin immunity has strong impact not only the local, but also on systemic immunity. However, fundamental mechanisms that underlie intricate regulation of leukocyte homeostasis and immune responses in skin remain understudied. We explore two important aspects of skin immunity: 1. Hair follicle (HF) immunology: We previously determined that HF are capable of recruiting and regulating the trafficking of skin dendritic cells via chemokine production upon sensing stress, establishing for the first time that the HF are immunologically functional. We are now in the process of demonstrating that not only HF recruit dendritic cells, but also that they support resident memory T cell persistence in skin by producing IL-7 and IL-15. CD8 T cells were dependent on HF-derived IL-15 and both CD4 and CD8 T cells were dependent on HF-derived IL-7. We further determined in a novel model for malignant lymphoma with skin infiltration that CD4+ lymphoma cells of resident memory T cell phenotype infiltrate the skin in HF-derived IL-7-dependent manner. 2. Mechanisms of microbiome-driven eczematous inflammation in mice: Staphylococcus aureus has been known to colonize atopic skin in humans, but whether this was the cause of skin inflammation or merely a result of chronic inflammation had been long debated. We recently developed a model in which mice exhibit eczematous dermatitis that closely resembles features of atopic dermatitis and that undergoes naturally occurring dysbiosis consisting of S. aureus and Corynebacterium species. Targeting dysbiotic flora via an antibiotic cocktail had both preventive and therapeutic effects on eczematous dermatitis, and notably, conserved microbial diversity. S. aureus primarily drove skin inflammation, whereas C. bovis enhanced T helper 2 responses that likely lead to elevated IgE in serum. Dysbiosis occurred as a result of impaired EGFR-signaling and epidermal Langherhans cells initiated innate immune responses against S. aureus. These results identified S. aureus as a critical component in eczema formation and provides implication for developing novel therapeutic strategies.
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