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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011561-02
Application #
9153984
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Voisin, Benjamin; Doebel, Thomas; Nagao, Keisuke (2018) A Hairy Tale of Monocytes and Contact Hypersensitivity Reactions. J Invest Dermatol 138:1251-1253
Woodring, Therese; Kobayashi, Tetsuro; Kim, Doyoung et al. (2018) ADAM17-Deficient Mice Model the Transcriptional Signature of Human Atopic Dermatitis. J Invest Dermatol :
Kobayashi, Tetsuro; Nagao, Keisuke (2018) Mapping regulatory circuits in allergic skin inflammation. Sci Immunol 3:
Kitashima, Daniela Y; Kobayashi, Tetsuro; Woodring, Therese et al. (2018) Langerhans Cells Prevent Autoimmunity via Expansion of Keratinocyte Antigen-Specific Regulatory T Cells. EBioMedicine 27:293-303
Doebel, Thomas; Voisin, Benjamin; Nagao, Keisuke (2017) Langerhans Cells - The Macrophage in Dendritic Cell Clothing. Trends Immunol :
Adachi, Takeya; Kobayashi, Tetsuro; Sugihara, Eiji et al. (2015) Hair follicle-derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma. Nat Med 21:1272-9
Kobayashi, Tetsuro; Glatz, Martin; Horiuchi, Keisuke et al. (2015) Dysbiosis and Staphylococcus aureus Colonization Drives Inflammation in Atopic Dermatitis. Immunity 42:756-66
Nagao, Keisuke; Segre, Julia A (2015) ""Bringing Up Baby"" to Tolerate Germs. Immunity 43:842-4
Nagao, Keisuke; Udey, Mark C (2015) Mushrooming insights into skin dendritic cell physiology. Immunity 42:210-3
Nagao, Keisuke (2014) p14 in control of Langerhans cell homeostasis. Blood 123:153-4