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FLG Deficiency in Mice Alters the Early-Life CD4+ T-Cell Response to Skin Commensal Bacteria
Jeanmarie R Gonzalez1, Anna Celli2, Antonin Weckel3
1Department of Dermatology, University of California San Francisco, San Francisco, California, USA; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, California, USA.
Abstract:
FLG variants underlie ichthyosis vulgaris and increased risk of atopic dermatitis, conditions typified by disruption of the skin microbiome and cutaneous immune response. Yet, it remains unclear whether neonatal skin barrier compromise because of FLG deficiency alters the quality of commensal-specific T cells and the functional impact of such responses. To address these questions, we profiled changes in the skin barrier and early cutaneous immune response of neonatal C57BL/6 Flg‒/‒ and wild-type mice using single-cell RNA sequencing, flow cytometry, and other modalities. Flg‒/‒ neonates showed little alteration in transepidermal water loss or lipid- or corneocyte-related gene expression. However, they showed increases in barrier disruption genes, epidermal dye penetration, and numbers of skin CD4+ T cells. Using an engineered strain of Staphylococcus epidermidis (S. epidermidis 2W) to study the response to neonatal skin colonization, we found that commensal-specific CD4+ T cells were skewed in Flg‒/‒ pups toward effector rather than regulatory T cells. This altered response persisted into adulthood, where it was typified by T helper 17 (Th17) cells and associated with increased susceptibility to imiquimod-induced skin inflammation. Thus, subtle but impactful differences in neonatal barrier function in Flg‒/‒ mice are accompanied by a skewed commensal-specific CD4+ response, with enduring consequences for skin immune homeostasis.
Insights
Filaggrin (FLG) deficiency in neonates alters skin barrier function, skewing immune responses to skin microbes. This early immune shift persists, increasing susceptibility to skin inflammation later in life.
Area of Science:
- Immunology
- Dermatology
- Microbiology
Background:
- Filaggrin (FLG) variants are linked to ichthyosis vulgaris and atopic dermatitis risk.
- These conditions involve skin microbiome disruption and altered cutaneous immunity.
- The impact of FLG deficiency on neonatal immune responses to skin commensals is not well understood.
Purpose of the Study:
- To investigate how neonatal skin barrier compromise due to FLG deficiency affects commensal-specific T cell responses.
- To determine the functional consequences of these altered immune responses on skin homeostasis.
Main Methods:
- Single-cell RNA sequencing and flow cytometry were used to profile skin barrier and immune responses in neonatal C57BL/6 Flg‒/‒ and wild-type mice.
- An engineered strain of Staphylococcus epidermidis (S. epidermidis 2W) was used to study responses to neonatal skin colonization.
- Changes in transepidermal water loss, gene expression, and T cell populations were analyzed.
Main Results:
- Flg‒/‒ neonates exhibited increased barrier disruption genes and epidermal dye penetration, with elevated skin CD4+ T cell numbers.
- Commensal-specific CD4+ T cells in Flg‒/‒ pups were skewed toward effector rather than regulatory T cells.
- This skewing persisted into adulthood, characterized by T helper 17 (Th17) cells, and was associated with increased susceptibility to imiquimod-induced skin inflammation.
Conclusions:
- Subtle neonatal barrier defects in FLG-deficient mice lead to a skewed commensal-specific CD4+ T cell response.
- This altered immune response has lasting consequences for skin immune homeostasis and increases susceptibility to inflammatory conditions.
