Figure 1.

Cellular networks of CD1d-restricted NKT cells and their soluble factors in regulating skin inflammatory responses. Since the skin is constantly exposed to external stimuli such as pathogens and allergens, inflammatory immune responses occur when the skin barrier is broken. For example, during infection, endogenous glycolipids (i.e., β-GlcCer) induced by TLR signaling can stimulate CD1d-restricted NKT cells to produce large amounts of soluble factors such as cytokines that promote or regulate immune responses, contributing to maintaining skin homeostasis. Thus, CD1d-restricted NKT cells can link innate and adaptive immunity, despite the small number of these cells in the skin. In addition, CD1d-restricted NKT cells can regulate immune responses by interacting with non-immune cells (i.e., fibroblasts and keratinocytes) and immune cells (i.e., Langerhans cells, dermal DCs, Breg cells, and B1 cells) during skin inflammation. Furthermore, staphylococcal superantigens (SsAgs), such as staphylococcal enterotoxin B (SEB), bind to both MHC II expressed on APC and TCR Vβ8 chain of CD1d-restricted NKT cells, consequently bridging interaction between APC and NKT cells via antigen-independent manner. Thus, TCR Vβ8-expressing NKT cells might be involved in regulating S. aureus pathogenesis in the skin even without glycolipid antigens. Moreover, upon cross-talk with various cell types, CD1d-restricted NKT cells produce soluble factors (e.g., IFNγ, IL2, IL4, IL13, TNFα, perforin, and granzymes), which are either protective or pathogenic in inflammatory skin diseases. AD, atopic dermatitis; ACD, allergic contact dermatitis; APC, antigen-presenting cells; β-GlcCer, β-D-glucopyranosylceramide; Breg cells, regulatory B cells; DCs, dendritic cells; LCs, Langerhans cells; SsAgs, staphylococcal superantigens.