The multifaceted role of XCL1 in health and disease

The chemokine XC motif chemokine ligand 1 (XCL1) is an unusually specialized member of a conserved family of around 50 small, secreted proteins that are best known for their ability to stimulate the directional migration of cells. All chemokines adopt a very similar folded structure that binds a specific G protein-coupled receptor (GPCR), and most chemokines bind extracellular matrix glycosaminoglycans, often in a dimeric or oligomeric form. Owing in part to the lack of a disulfide bond that is conserved in all other chemokines, XCL1 interconverts between two distinct structures with distinct functions. One XCL1 fold resembles the structure of all other chemokines (chemokine fold), while the other does not (alternate fold). The chemokine fold of XCL1 displays high affinity for the GPCR XCR1, while the alternative fold binds GAGs and exhibits antimicrobial activity. Although the canonical role of XCL1 as a CD8+ dendritic cell chemoattractant was defined more than a decade ago, the misconception that XCL1 is a lymphocyte-specific chemoattractant still prevails in the recent literature. This review aims to highlight the structure-guided functions of XCL1 and reclarify its immunological role. In addition, the implications of this metamorphic chemokine in vaccine development and emerging functions in the nervous system will be explored.