Unraveling skin microbiota-immune interactions that drive early life commensal tolerance - research project summary the skin is a vital barrier tissue, which manages to maintain immune homeostasis…

The National Institute of Allergy and Infectious Diseases awarded The Regents of the University of California, San Francisco $222,085 on October 24, 2025, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to conduct research on skin microbiota-immune interactions that drive early life commensal tolerance.

The research investigates how cutaneous immune cells maintain tolerance to skin commensal microbes while defending against pathogens, with focus on the role of CD301B+ type 2 dendritic cells in generating commensal-specific regulatory T cells through retinoic acid production. The project examines how conserved microbial ligands, particularly d-alanine modifications of bacterial surface teichoic acids sensed through toll-like receptor 2, reinforce tolerogenic function in dendritic cells. The work addresses mechanisms underlying chronic inflammatory skin diseases including acne vulgaris, atopic dermatitis, and hidradenitis suppurativa, using in vivo and ex vivo studies with mutant Staphylococcus epidermidis strains and neonatal mouse models to identify commensal signals that support immune tolerance.

Work is performed in San Francisco, California, with performance period through November 6, 2026. The project grant is classified as assistance type Project Grant.

Unraveling skin microbiota-immune interactions that drive early life commensal tolerance - research project summary the skin is a vital barrier tissue, which manages to maintain immune homeostasis amidst ongoing microbial stimulation. Cutaneous immune cells continually sense skin commensal microbes, yet a healthy symbiosis is preserved through mechanisms that actively regulate this commensal-specific immune response. Disruption of this tolerance contributes to chronic inflammatory diseases such as acne vulgaris, atopic dermatitis and hidradenitis suppurativa. Prior work from my lab has highlighted that early exposure to skin bacteria promotes immune tolerance through the generation of commensal-specific regulatory t cells (tregs). Recent studies specifically identified CD301B+ type 2 dendritic cells (DC2) as the primary population sampling commensal bacteria in neonatal skin and critically supporting generation of commensal-specific tregs. The treg-promoting function of CD301B+ DC2 is facilitated by their retinoic acid production, which is further augmented upon uptake of commensal bacteria. However, many questions remained from this work, most notably, what are the commensal signals that reinforce tolerogenic function in CD301B+ DCS and how are these sensed? Preliminary data i'VE generated since starting my PHD have started to address this knowledge GAP. I have shown that in vivo deletion of toll like receptor 2 (TLR2) leads to greatly reduced commensal-specific tregs in neonatal mice. Additionally, through in vivo and EX vivo studies using mutant staphylococcus epidermidis strains, i have seen that fewer commensal-specific tregs are generated by CD301B+ DC2 in response to bacteria lacking d-alanine modification of their surface teichoic acids, known ligands for TLR2. Collectively, these results shed new light on the role of conserved microbial ligands not only as stimulators of cutaneous immune defense against pathogens but also as fundamentally supporting commensal-specific immune tolerance. Building on these solid lines of evidence, this project will investigate how TLR2 sensing of modified ligands on commensal staphylococcus SPP. Supports treg induction by CD301B+ DC2S. Aimed at dissecting these mechanisms and furthering my training goals, i will employ a combination of approaches, including transgenic mouse models, genetic manipulation of bacterial strains, and human skin explants. Collectively, these studies will deepen our understanding of skin immune tolerance, potentially inform therapeutic targets for inflammatory diseases and advance me towards my long-term career goal of becoming an independent investigator and academic educator studying host-microbe interactions.