Lymphocyte homing directs lymphocyte subsets to specialized microenvironments and targets immune effector cells in a tissue specific fashion, focusing regional immune responses. The molecules mediating the multi-step paradigm for lymphocyte homing have been described in detail for peripheral tissues such as the skin and gut (Kunkel EJ, et al. Immunity 2002; 16:1-4). However, in the liver, the molecules involved have not been well defined. In my studies of liver homing molecules under the K08 grant, I identified an important role for chemokine receptor/ligand pair, CXCR6 and CXCL16, in selectively recruiting activated CD8 cells to the liver. By using a well-established animal model of GVHD (C57BL/6 into BDF1), I compared the development of disease and recruitment of activated donor cells into the liver by wild-type and CXCR6-deficient donor cells and found chemokine receptor deficient CD8 cells migrated into the liver less efficiently. The removal of one chemokine receptor decreased recruitment significantly but not completely, suggesting other chemokine receptors working serially or synergistically with CXCR6. Several human liver diseases (i.e., hepatitis C, liver transplant allograft, and hepatocellular carcinoma) and animal models of liver disease, including GVHD, induce upregulation of CXCR3 and its ligands, CXCL9, 10, and 11. CXCR3 mediates adhesion and transmigration on endothial cell layers expressing its ligands, and cells isolated from Th1 mediated inflamed tissues express CXCR3 and migrate to its ligands. Previous studies show that inhibition of CXCR3 or its ligands affect accumulation of lymphocytes in the liver but do not distinguish between recruitment and the confounding factors of proliferation, apoptosis, or egress. By using the methods established from my studies of CXCR6, I plan to characterize the role of CXCR3 and its interplay with CXCR6 as liver homing molecules and possible therapeutic targets.
|Hadeiba, Husein; Sato, Tohru; Habtezion, Aida et al. (2008) CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease. Nat Immunol 9:1253-60|
|Lin, Francis; Baldessari, Fabio; Gyenge, Christina Crenguta et al. (2008) Lymphocyte electrotaxis in vitro and in vivo. J Immunol 181:2465-71|