Beyond Drainage: How Lymphatic Vessels Instruct Immune Cell Fate

Lymphatic vasculature is increasingly recognized as not only a passive drainage network but also an active regulator of immune cell fate. This regulation operates through two complementary modes. In the direct mode, lymphatic endothelial cells engage immune cells through checkpoint signaling, antigen presentation, and adhesion-dependent transendothelial migration, thereby regulating the deletion, anergy, and differential trafficking of regulatory and effector T cells. In the indirect mode, biomechanical cues (including interstitial flow, interstitial fluid pressure, and dynamic switching of endothelial junctions between button-like and zipper-like states), along with chemokine gradients, govern the selective delivery of immune cells and antigens to draining lymph nodes and the kinetics of this process. Both direct and indirect modes are shaped by the local tissue microenvironment, and their remodeling during inflammation and cancer can favor either immune priming or immunosuppression. When these two modes are considered as an integrated, coupled system rather than separate processes, the context-specific advantages and limitations of lymphatic-targeted immunomodulation can be evaluated.