In contrast, mice that are deficient in IL-15, or its receptor IL-15Rα, do not develop enlarged lymphoid tissues, increased serum immunoglobulin, or autoimmune disease. Rather they have a marked reduction in the number of thymic and peripheral natural killer (NK) cells, NK T cells, and intestinal intraepithelial lymphocytes. Thus, IL-15Rα-deficient mice show a marked reduction in CD8CD44 memory T cells. The differences of the function of IL-2 and IL-15 reflect the distinct modes of actions of these two cytokines. IL-2 functions as a secreted cytokine, acting on preformed heterotrimeric receptors expressed on activated T and NK cells. In contrast, IL-15 and IL-15Rα expressed on the surface of antigen-presenting cells are presented in trans to CD8 T cells and NK cells that express only the β and γ chain of the IL-15 receptor.