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Understanding immunity through the architecture of the epidermis

The skin is not only a physical barrier against the external environment but also a site where the immune system learns to distinguish self from foreign antigens. Our research focuses on loricrin, a key protein of terminal epidermal differentiation, and explores the concept of “structural immunity”: the idea that tissue architecture helps shape immune tolerance and memory.

In healthy skin, continuous epidermal renewal is coordinated with interactions among keratinocytes, antigen-presenting cells, and T cells. Using loricrin-deficient mice, we have found that altered epidermal differentiation is associated with changes in antigen-presentation environments, the repertoire structure of regulatory T cells (Tregs), and immune responses to ultraviolet irradiation. Building on these observations, we investigate how self-antigens are presented and how appropriate T-cell clones are selected. A particular focus is the relationship between immune education during early postnatal development and inflammatory or antitumor responses later in life. The proposed mechanisms linking stable self-peptide–MHC class II presentation to regulatory clone selection remain under investigation.

Our work also addresses clinically important skin diseases, including atopic dermatitis, psoriasis, hidradenitis suppurativa, autoimmune disorders, melanoma, and other skin cancers. We study how local tissue environments influence persistent inflammation, immune surveillance, therapeutic responses, and recurrence. By integrating dermatology, immunology, and patient-oriented research, we aim to translate fundamental discoveries about tissue organization into a better understanding of disease and new therapeutic strategies.

Figure: “Epidermal differentiation as a foundation for immune tolerance,” illustrating antigen presentation and T-cell selection in healthy and structurally altered epidermis.