The Critical Role of Induced CD4+ FoxP3+ Regulatory Cells in Suppression of Interleukin-17 Production and Attenuation of Mouse Orthotopic Lung Allograft Rejection.

Abstract

Lung transplantation is the only definitive therapy for many forms of end-stage lung disease. Studies have demonstrated the critical role of interleukin (IL)-17 in the development of lung rejection. Regulatory T cells (Tregs) are essential for the establishment and maintenance of immune tolerance. We established mouse orthotopic lung transplantation models to investigate the importance of IL-17 and IL-17-producing cell types in acute lung allograft rejection and the efficacy of the adoptive transfer of induced Tregs (iTregs) in attenuating pathologic lesions of lung allografts. We found that the IL-17 produced by Th17 cells and γδ T cells might make the primary contributions to the progression of acute lung allograft rejection. Interleukin-17 deficiency decreased lung allograft lesions. Exogenous iTregs maintained their FoxP3 expression levels in lung allograft recipients. Induced Tregs therapy downregulated the expressions of Th17 and IL-17 γδ T cells and increased IL-10 production in the mouse orthotopic lung transplantation models. Moreover, the adoptive transfer of iTregs prolonged the survivals of the lung allografts and attenuated the progression of acute rejection. These data suggested that the adoptive transfer of iTregs could suppress the Th17 cells and IL-17 γδ cells of the recipients, decrease the expression of IL-17, and attenuate the pathology of acute lung allograft rejection. Exogenous iTregs upregulated immunosuppressive factors, such as IL-10 and suppressed IL-17-producing cells, which was one of the pathways to play a role in protecting lung allografts.