Obliterative bronchiolitis (OB) is one of the main complications affecting long-term survival of post-lung transplantation patients. In this study, we evaluated the efficacy of Tk-PQ (a peptide derived from trichosanthin) in alleviating OB in a mouse ectopic tracheal transplant model. We found that post-transplantation treatment of Tk-PQ significant ameliorated OB symptoms including luminal occlusion, epithelial cells loss and fibrosis in the allograft. In addition, Tk-PQ promoted immune suppressive environment by inducing Th2 polarization and increasing Treg population which in turn led to elevated levels of anti-inflammatory cytokines IL-4, IL-10, IL-33 and decreased levels of pro-inflammatory IL-1β. Mechanistically, we used transcriptome analysis of splenic T cells from allografted mice to show that Tk-PQ treatment down-regulated the PI3K-Akt signaling pathway. Indeed, the immune suppression phenotypes of Tk-PQ was recapitulated by a PI3K inhibitor LY294002. Taken together, Tk-PQ regulates post-transplantation immuno-rejection by modulating the balance of T cell response via the PI3K-Akt pathway, making it a promising peptide based immune rejection suppressant for patients receiving allotransplant.