Elucidating the Role of the Skin Barrier Protein Filaggrin in the Adaptive Immune Response to Commensals

Abstract

Atopic dermatitis (AD), commonly known as eczema, is a chronic inflammatory skin disease that affects millions of Americans. While there are both genetic and environmental components, one of the key factors is disruption of skin barrier physiology. In particular, mutations in the filaggrin are found in up to 40% of patients and predispose them to severe, early onset AD and later progression along the atopic march. Filaggrin is expressed in the upper layers of the skin epithelium and contributes to maintenance of skin pH and moisturization, critical for maintaining the structural function of the epidermis. The skin barrier is also important for regulating the response to bacteria. In AD, disease flares are also associated with an altered skin microbiome, with increases in Staphylococcus epidermidis (S. epi), a skin commensal, and Staphylococcus aureus, a pathobiont. There are many open questions about what role impaired skin epithelial barrier function plays in the adaptive immune response to commensals like S. epi, and how this may contribute to disease. I hypothesize that early life deficiency of skin barrier function alters the quality of the commensal-specific T cell response, which contributes to later pro-inflammatory responses to these bacteria. Antigen specific T cell responses are difficult to study due to the rarity of individual T cell clones, so our lab uses a novel system allowing tracking of CD4+ T cells specific for S. epi. I have found that mice lacking filaggrin (flg-/-) differ from wildtype (wt) controls in their immune response to this commensal. Our lab has previously shown that wt mice colonized early in life develop immune tolerance to S. epi via enrichment of antigen-specific regulatory T cells (Tregs), an immune cell population that controls inflammation. This new work shows that in several models of S. epi colonization, flg-/- mice elicit reduced frequencies of commensal antigen-specific Tregs compared to wt counterparts. This project also focuses on elucidating the mechanistic basis of this key finding and determining its contribution towards propensity for skin and systemic type-2 inflammation. In summary, our work suggests that skin barrier physiology significantly impacts the quality of the commensal-specific CD4+ response early in life, which may have enduring consequences for skin immune homeostasis.