Therapy with WT APC or signaling-selective 5A-APC improves GVHD/BO and requires arginine 46 (R46) in PAR1 expressed on donor T cells. B10.BR (H2^k) mice were conditioned with 120 mg/kg cyclophosphamide for 2 days, followed by 830 cGy TBI. On day 0, mice were transplanted with C57BL/6 (H2^b) T-cell depleted BM and purified splenic T cells (7 × 10⁴). Mice were allowed to develop disease and were treated daily with 6 µg of recombinant murine WT APC (A-B) or 5A-APC (C-D; abbreviated herein as APC) intraperitoneally from days 28 to 56. (A,C) Pulmonary function tests were performed on day 56 by measuring resistance and compliance after treatment. (B,D) Spleens of BM-only (no cGVHD) or cGVHD mice, treated as indicated, were analyzed on day 56 for the frequency of TFHs, frequency of TFRs, and TFR/TFH ratio. Three (A) or 2 (C) experiments were performed for pulmonary function, and 1 experiment was performed for flow cytometry with 4 or 5 mice analyzed per group (B,D). (E) Sheep red blood cells (SRBCs) were administered intraperitoneally (n = 4-6 mice per group). Seven days later, spleens and sera from naive or SRBC-immunized WT, arg46 (R46Q), or arg41 (R41Q)–mutated mice were analyzed. Data are mean ± standard error of the mean. *P < .05, **P < .01, ***P < .001, ****P < .0001.