Fig. 2

a The structure and immune cell distribution of the skin under steady state. The epidermis represents the outermost layer of the skin. The dermis can be divided into the superficial papillary layer and the deeper reticular layer. Blood and lymphatic vessels, as well as nerves (not shown), pervade the dermis. Under normal conditions, the most common immune cells in human epidermis are LCs, located in the stratum spinosum, and CD8⁺ tissue-resident memory T (TRM) cells, found in the stratum basale and stratum spinosum [70]. CD8⁺ TRM cells can migrate between the epidermis and the papillary dermis, performing tissue patrols [71]. The mouse epidermis contains dendritic epidermal T cells (DETCs), a cell type absent in humans. In healthy skin, dermal leukocytes encompass DCs, macrophages, mast cells, γδ T cells, natural killer (NK) cells, innate lymphoid cells (ILCs), αβ T cells, and B cells. Most αβ T cells in the dermis are CD4⁺ T cells, while B cells are rarely present in normal skin [72]. Skin appendages include hair follicles, sebaceous glands, and sweat glands (not shown). Commensal microorganisms inhabit the epidermis, dermis, and dermal appendages, forming an additional layer of host defense [73]. b Epithelial composition and immune cell distribution of the intestine under steady state. The intestinal epithelium is composed of a single layer of cells, arrayed into projections known as villi which extend into the intestinal lumen, and moat-like invaginations called crypts that surround the villi. Multipotent stem cells are located at the base of these crypts, interspersed among Paneth cells. These stem cells have the capability to differentiate into intestinal absorptive cells and all types of specialized epithelial cells, including goblet cells, Paneth cells, microfold-cells (M-cells), and tuft cells [74]. Intraepithelial lymphocytes (IELs) display high levels of activity. They are typically situated between the basement membrane and the epithelial layer of the intestinal villi under steady-state conditions, occasionally demonstrating transient movements closely associated with epithelial cells [75]. Peyer’s patches (PPs) are unique tertiary lymphoid organs in the small intestine, and isolated lymphoid follicles (ILFs) are distributed along the length of both the small and large intestines. Compared to the small intestine, the colonic epithelium lacks villi structures and IELs are rarely observed. Paneth cells are typically found only in the small intestine, but are present in the colon during inflammatory conditions. The lamina propria is composed of loose connective tissue traversed by blood vessels, lymphatic vessels, and nerves (not shown), and houses numerous innate and adaptive immune cells. M-cells, macrophages, and dendritic cells (DCs) are responsible for sampling antigens and triggering specific T cell and B cell responses within GALT