Beyond providing barrier function, extracellular lipids in human skin are thought to play an immunological role, since we have previously shown that small hydrophobic lipids present in sebaceous glands and stratum corneum can function as antigens for CD1a-restricted T cells. Recent publications showing a central role for CD1a in skin inflammatory conditions such as psoriasis and allergic contact dermatitis, suggest that CD1a-restricted T cells can have an immunopathogenic role. Yet, their presence in healthy skin, together with CD1a^high Langerhans cells and an abundance of antigenic lipids, suggests that under homeostatic conditions, mechanisms must be in place to regulate the activation of CD1a-restricted T cells. Our research focuses on the nature of potential regulatory mechanisms, including influence of 1) relative amounts of antigenic lipids and non-antigenic lipids competing for CD1a binding 2) the effects of common skin commensals/pathogens, and 3) expression of inhibitory receptors on CD1a-autoreactive T cells.  Addressing the first mechanism using cell-based and cell-free plate-bound CD1a protein and CD1a-restricted T cell lines, we have preliminary evidence that ceramides, which are the most abundant extracellular lipids in human skin, can displace antigenic lipids from CD1a, thereby inhibiting lipid-specific T cell activation. Ceramides with long acyl chains more effectively displaced the antigenic lipids than shorter chain analogs. This is potentially relevant in atopic dermatitis, where not only the total amount of ceramides, but also specifically longer chain ceramides are reduced. Our recently initiated investigation in atopic dermatitis patients and controls, aims to determine if a relative reduction in non-antigenic ceramides in stratum corneum is correlated with increased frequencies and activation of CD1a-autoreactive T cells in the skin. This would support the notion that the shifts in skin lipid composition observed in this inflammatory skin disease, in particular a decrease in non-antigenic CD1a binding lipids, may partially underlie increased T cell activation in the skin.