Tertiary Lymphoid Organs Orchestrate Altered Gut to Lymph Node Communication Through Association With Collecting Lymphatic Vessels

Abstract

Tertiary lymphoid organs often arise during chronic inflammation, including in inflammatory bowel diseases like ileitis. The impact of TLOs on disease progression or immunity and how they integrate with or influence the surrounding tissue microenvironment remain unclear. In human Crohn's disease, we earlier observed that TLOs were positioned along mesenteric collecting lymphatic vessels (CLVs) that govern lymph outflow from the intestine. Here we show in the TNFΔARE mouse model of Crohn’s-like ileitis that TLOs form at valve regions of CLVs, supporting lymphangiogenic outgrowths. These TLOs compress CLVs, preventing forward lymph flow and immune cell egress to draining lymph nodes, while fostering lymph leak and backflow. Lymph transport through TLOs was restored if TNF neutralization was begun early. However, robustly developed TLOs resisted regression and restoration of flow. Thus, TLOs can profoundly remodel communication between tissues and their draining lymph nodes by strongly suppressing dissemination of cells and molecules.