Although predominantly expressed on lymphocytic and hematopoietic cells, the role of sphin‐gosine‐1‐phospate receptor 4 (S1P ₄ ) in immune homeostasis is still poorly understood. In this report, we used a S1P ₄ ‐deficient murine model to characterize the biological role of S1P ₄ ‐mediated S1P signaling in the immune system. S1p ₄ ^‐/‐ animals showed normal peripheral lymphocyte numbers and a regular architecture of secondary lymphoid organs. Interestingly, S1P ₄ only marginally affects T‐cell function in vivo. In contrast, dendritic cell (DC) migration and cytokine secretion are profoundly affected by S1P ₄ deficiency. Lack of S1P ₄ expression on DCs significantly reduces T _H 17 differentiation of T _H cells. Furthermore, in various in vivo models of T _H 1‐ or T _H 2‐dominated immune reactions, S1P ₄ deficiency consistently increased the amplitude of T _H 2‐dominated immune responses, while those depending on T _H 1‐dominated mechanisms were diminished. Finally, S1p ₄ ^‐/‐ mice showed decreased pathology in a model of dextran sulfate sodium‐induced colitis. In summary, for the first time, we show that S1P ₄ signaling is involved in the regulation of DC function and T _H 17 T‐cell differentiation. S1P ₄ ‐mediated S1P signaling also modifies the course of various immune diseases in a murine model. We propose that S1P ₄ may constitute an interesting target to influence the course of various autoimmune pathologies.—Schulze, T., Golfier, S., Tabeling, C., Räbel, K., Gräler, M. H., Witzenrath, M., Lipp, M. Sphingosine‐1‐phospate receptor 4 (S1P ₄ ) deficiency profoundly affects dendritic cell function and T _H 17‐cell differentiation in a murine model. FASEB J. 25, 4024–4036 (2011). www.fasebj.org

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