Rapid activation of lymph node lymphangiogenesis (IRC4P.458)

Abstract

Abstract The lymphatic system delivers fluid and molecules from tissues to the lymph node (LN) to mediate immune system surveillance of self and foreign antigens. LN lymphatic endothelial cells (LECs) function in orchestration of the immune response, and in reinforcement of peripheral tolerance. Extensive LN lymphatic sinus growth (lymphangiogenesis) is involved in multiple diseases including cancer, arthritis, and inflammation. Lymphocytes and leukocytes regulate this lymphangiogenesis; however, the mechanism is not well defined. We identified a monoclonal antibody (10.1.1) that recognizes the LEC protein mCLCA1. Our studies identified mCLCA1 as an interacting partner for LFA-1 and Mac-1 that mediates lymphocyte and leukocyte adhesion. The 10.1.1 Ab blocks adhesion of lymphocytes to LECs in vitro to a greater extent than ICAM-1 neutralizing Ab, suggesting that while ICAM-1 interactions predominate in vascular endothelium, mCLCA1 interaction is more important for adhesion to LECs. In addition to mediating adhesion, the 10.1.1 Ab (but not control Ab) induces rapid LN lymphangiogenesis within 23 hours after injection into mice, which involves proliferation of LN LECs. This lymphangiogenesis is accompanied by LN remodeling involving multiple stromal cell types, resembling the LN response to inflammation. These findings suggest that 10.1.1 Ab mimics lymphocyte or leukocyte B2-integrin binding to LEC mCLCA1, to drive LN remodeling and lymphangiogenesis during immune responses.