Growing evidence suggests that the neuropeptide Y (NPY) system plays an important role in the immune system. Yet, little is known about the expression of NPY and receptors in the immune system. Moreover, original contradicting results have confused the picture and hampered a clear understanding of its role in the immune system. The use of Y1 receptor-deficient mice, combined with advanced methods to investigate immune functions, have provided the solution to the problem raised by previous disparities. From results obtained using Y1-deficient mice (Symbol), we uncovered a bimodal role for Y1 on immune cells. Y1 expression on antigen-presenting cells (APC) is essential for their function as T cell priming elements. Conversely, Y1 signaling in T cells plays a regulatory role without which T cells are hyper-responsive. The opposite role of Y1 on APC and T cells has reconciled previous disparities by showing that signaling via Y1 protects against inflammation by inhibiting T cell responses, whereas Symbol mice are protected in the same inflammatory models due to defective APCs.