Regulation of immune responses by crosstalk between T cells and lymphatic endothelial cells

Abstract

Part 1. Th2 cells and their cytokines regulate formation and function of lymphatic ves-sels Lymphatic vessels (LVs) play an important role in immune surveillance by regulating immune cell migration and antigen delivery to draining lymph nodes (LNs). In the present study, we investigated the effects of the T helper type 2 (Th2) cell effector cytokines, IL-4 and IL-13, on lymphangiogenesis. We showed that treatment of mouse lymphatic endothelial cells (mLECs) and human LECs (hLECs) with IL-4 and IL-13 down-regulated expression of Prox-1, an essential transcription factor expressed by LECs. IL-4 and IL-13 also inhibited tube formation by LECs in vitro. Similarly, LECs co-cultured with Th2 cells showed decreased tube formation, and this effect was fully restored by cytokine neutralization with anti-IL-4 and anti-IL-13 antibodies. In allergen-induced asthma models, we assumed that airway LVs would be increased since asthma is an inflammatory disease, however, we failed to observe an increase in lymphatics of the airways. Moreo-ver, in this case, in vivo blockade of IL-4 and IL-13 increased not only the density of LVs, but also the function of LVs in the airways. Taken together, our findings indicate a novel anti-lymphangiogenic function for Th2 cells via production of IL-4 and IL-13.

Part 2. Regulation of $CD4^{+} T$ cell differentiation by CD25 which is expressed on lym-phatic vessels LECs are known to regulate the trafficking of dendritic cells and lymphocytes be-tween tissues and secondary lymphoid organs. In this study, we investigated the novel role of CD25 which is expressed on LECs in $CD4^{+} T$ cell regulation. We showed that CD25, CD122 and CD132, which are components of IL-2 receptor, are expressed on LECs. However, IL-2 did not show any effect on Prox-1 and LYVE-1 expression in LECs. Fi-nally, we showed that CD25 of LECs controlled $CD4^{+} T$ cell differentiation during primary stimulation. Taken together, our findings suggest an unidentified function of LECs to control regulatory T cell (Treg cell) differentiation via CD25.