ICOS blockade inhibits GVHD independent of CD28, STAT4, or STAT6 signaling. (A) Lethally irradiated (8.0 Gy) BR mice received 20 × 10⁶ B6 BM (^*) and 15 × 10⁶ B6 CD28^-/- splenocytes. Irrelevant rIgG (•) or anti-ICOS (○) was administered from day -1 through day 28. Survival is shown (n = 8/group; P = .009). KO indicates knock out. (B) Lethally irradiated B6 (9.0 Gy) mice received 20 × 10⁶ BALB/c BM (^*) and 25 × 10⁶ splenocytes from BALB/c WT (circles), STAT4^-/- (squares), or STAT6^-/- mice (triangles). Irrelevant mAb (filled symbols) or anti-ICOS (open symbols) was administered from day -1 through day 28. Survival is shown (n = 8/group; P ≤ .0075, irrel mAb vs anti-ICOS for each spleen donor).