Dissecting the complexity of γδ T-cell subsets in skin homeostasis, inflammation, and malignancy

gamma delta T cells are much less common than ab T cells, accounting for 0.5% to 5% of all T lymphocytes in the peripheral blood and lymphoid tissues in mice and humans. However, they are the most abundant T-lymphocyte subset in some epithelial barriers such as mouse skin. gd T cells are considered innate lymphocytes because of their non-MHC restricted antigen recognition, as well as because of their rapid response to cytokines, invading pathogens, and malignant cells. Exacerbated expansion and activation of gd T cells in the skin is a common feature of acute and chronic skin inflammation such as psoriasis and contact or atopic dermatitis. Different gd T-cell subsets showing differential developmental and functional features are found in mouse and human skin. This review discusses the state of the art of research and future perspectives about the role of the different subsets of gd T-cells detected in the skin in steady-state, psoriasis, dermatitis, infection, and malignant skin diseases. Also, we highlight the differences between human and mouse gd T cells in skin homeostasis and inflammation, as understanding the differential role of each subtype of skin gd T cells will improve the discovery of new therapies. (J Allergy Clin Immunol 2021;147:2030-42.)