A Novel α9 Integrin Ligand, XCL1/Lymphotactin, Is Involved in the Development of Murine Models of Autoimmune Diseases

The integrin alpha 9 beta is a key receptor involved in the development of autoimmune diseases. However, the detailed mechanism for the association of alpha 9 beta 1 integrin with its ligands remains unclear. In this study, we introduce XCL1/lymphotactin, a member of the chemokine family, as a novel ligand for alpha 9 integrin. Using alpha 9 integrin-overexpressing NIH3T3 cells and endogenously alpha 9 integrin-expressing human rhabdomyosarcoma cells, the interaction between XCL1 and alpha 9 integrin was confirmed by pulldown assays. XCL1 enhanced alpha 9 integrin-dependent cell migration of these cells, thus acting on alpha 9 integrin as a chemoattractant. We also analyzed the in vivo function of XCL1 in the development of anti-type II collagen Ab-induced inflammatory arthritis (CAIA) in BALB/c mice and experimental autoimmune encephalomyelitis in C57BL/6 mice, because alpha 9 integrin is involved in these autoimmune disease models. In CAIA, recombinant XCL1 aggravated the disease and this exacerbation was inhibited by an anti-alpha 9 integrin Ab. An XCL1-neutralizing Ab produced in this study also ameliorated CAIA. Furthermore, the XCL1neutralizing Ab abrogated the disease progression in experimental autoimmune encephalomyelitis. Therefore, to our knowledge this study provides the first in vitro and in vivo evidence that the interaction between XCL1 and alpha 9 integrin has an important role for autoimmune diseases.