Deciphering the Th2 Cell Niche in Atopic Dermatitis

• Applicant: Dr. Thomas Gan
• Subject Area: Dermatology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 538205505

Tissue resident lymphocytes play major roles in health and disease. Many of these cells first establish themselves in peripheral (i.e., non-lymphoid) organs during precise windows of early postnatal development and are maintained within specific microanatomic tissue niches, where they participate in host defense, prevent tumor development and facilitate tissue repair. Dysfunction of tissue resident lymphocytes and/or their anatomic niches is thought to contribute to chronic tissue inflammation. Understanding how these cells are established and maintained in tissues is of fundamental importance in our attempts to functionally manipulate them for therapeutic benefit. Regulatory T cells (Tregs) are a subset of lymphocytes that play an integral role in establishing and maintaining immune homeostasis in tissues. We previously found that a specialized population of Tregs migrates into murine skin during a defined window of neonatal life (termed neonatal Tregs or 'neoTregs') where they play a major role in promoting adaptive immune tolerance to skin commensal microbes. We have recently discovered that neoTregs facilitate normal skin development. Specifically, we have found that transient depletion of Tregs in neonatal mice results in the aberrant accumulation of a novel subset of stromal cells that express multiple pathways involved in type 2 immune responses (termed 'type 2 stromal cells’ or ‘type 2 SCs’). Concurrently, a population of Th2 cells establishes residence in the same region of skin as type 2 SCs and persists long after neoTreg depletion. We hypothesize that neoTreg dysfunction early in life predisposes to aberrant Th2 immune responses in adulthood by facilitating the establishment of a pathogenic Th2 cell niche in skin. Humans with congenital loss of Tregs have dysregulated Th2 immune responses in skin and develop severe atopic dermatitis (AD). Thus, we further postulate that Treg dysfunction early in life contributes the development of human AD and that augmenting Tregs in AD skin will preferentially suppress Th2 immunity. To test these hypotheses, we propose the following specific aims: 1) Identify the cellular and molecular factors necessary for the establishment and maintenance of a Th2 cell niche in skin. 2) Determine if neoTreg dysfunction early in life predisposes to atopic inflammation and aberrant microbial responses in adulthood. 3) Define the Treg-Stromal Cell-Th2 axis in patients with AD and determine if Treg augmentation preferentially suppresses Th2 immunity in AD skin. The experiments outlined in this proposal represent an innovative, systematic, and multifaceted approach to elucidate how immune cell niches are established and maintained in peripheral tissues. We aim to functionally test novel hypotheses linking regulatory T cell and skin stromal cell biology. Insights gained may have a major impact on our understanding of human disease, with a focus on atopic inflammation.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Michael Rosenblum