IL-15 is coordinately expressed with IL-15 Rα in acute GVHD. (A) Rationale behind the mixed BM cell experiment. Wild-type B6 control donor BM cells can produce IL-15 for presentation by IL-15 Rα. IL-15^–/– and IL-15 Rα^–/– control donor BM cells are each genetically deficient in IL-15 signaling and each confers a survival benefit compared with wt B6 BM cells. In postulate 1, IL-15 Rα^–/– donor BM cells produce IL-15 whereas IL-15^–/– donor BM cells have IL-15 Rα. Because it is postulated that the same cell must produce and present IL-15, it is expected that survival will not be adversely affected in the mixed BM group. In postulate 2, coordinate production and presentation is not required. Thus, IL-15 Rα^–/– donor BM cells produce IL-15, which is captured and presented by IL-15^–/– donor BM cells, thereby restoring IL-15 signaling and reducing or eliminating any survival benefit in the mixed BM group compared with wt B6 control. (B) Lethally irradiated wt B6D2F1 mice (n = 5 per group) underwent transplantation with 5 × 10⁶ wt B6 splenic T cells and 1 × 10⁷ TCD BM cells from either wt B6 (▪), IL-15^–/–B6 (□) or IL-15 Rα^–/– B6 mice (▵). A fourth cohort of mice underwent transplantation with 1 × 10⁷ TCD BM cells from IL-15^–/– and IL-15 Rα^–/– B6 mice mixed at a 1:1 ratio (○). Survival times were compared using the logrank test and results were consistent with postulate 1.