Exploring mechanisms that govern immune homeostasis in skin

Division Of Basic Sciences - Nci

Investigators

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Abstract

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. Furthermore, elucidating stromal cell-mediated immune homeostasis should have impact on how cancer cells regulate or evade the immune system. Fundamental mechanisms that underlie intricate regulation of leukocyte homeostasis and immune responses in skin remain understudied. We explore the below important aspects of skin immunity: 1) The role of hair follicles and other stromal cells in regulating skin-resident leukocytes We previously determined that hair follicles 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 have recently demonstrated (Nature Medicine, 2015) that not only do HF recruit dendritic cells, but they also 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. The IL-7-IL-7 receptor axis appears to be operation in human malignant lymphoma of the skin. These findings provide clinical implications for designing new therapeutic strategies that target IL-7 or IL-7 receptor signaling in malignant lymphoma in the skin or other inflammatory skin diseases mediated by resident memory T cells. We are in the process of gaining a broader view on the various leukocyte subsets that reside in the skin and are exploring the mechanisms that govern their residency by interacting with not only hair follicles but also other stromal cell subsets. 2) Mechanisms of microbiota-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 (Immunity, 2015). 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. Studies on immunological pathways downstream of dysbiosis are underway.