Background: The long-term success of lung transplantation is mainly limited by the development of obliterative bronchiolitis (OB) in which IL-17 plays a critical role. Direct evidence of IL-17-mediated allograft rejection has only been observed when T-bet is absent. However, lack of T-bet also leads to failure in production of IFNγ which is required for tolerance induction and allograft acceptance, as T-bet deficiency results in IL-17-expressing CD8⁺ T cells mediated costimulation blockade-resistant allograft rejection. Our previous research demonstrated that T-bet/STAT6 double deficiency favored Th17-dominant immune responses, and importantly, restored some IFNγ production. Here we investigated whether T-bet/STAT6 DKO mice as allograft recipients could provide a useful model to study Th17 and IL-17 in lung transplantation.

Methods: Murine orthotopic allogeneic lung transplants were performed in C57BL/6 wild type and T-bet/STAT6 DKO mice using BALB/c donors. At day 10, histopathologic characteristics and rejection status of transplanted grafts were assessed; graft-infiltrating cells were isolated and real-time RT-PCR was performed for IL-17, IFNγ and IL-4 expressions.

Results: Allografts of both wild type and DKO recipients displayed vigorous acute rejection and expressed comparable levels of IFNγ; while T-bet/STAT6 double deficiency resulted in much more IL-17 and less IL-4 production. Histopathologic examination demonstrated that allografts of both wild type and DKO recipients have marked inflammatory cell infiltration and pulmonary parenchyma lesion. In contrast to lymphocyte-predominant inflammation observed in wild type recipients, allografts of DKO recipients displayed obvious polymorphonuclear cell infiltration and obliterative airway inflammation. Compared to wild type recipients, the ratio of graft-infiltrating CD8⁺ versus CD4⁺ T cells increased significantly with much higher numbers of neutrophils in allografts of DKO recipients.

Conclusion: T-bet/STAT6 DKO recipients of lung allografts result in IL-17-dominant transplant immunity, retain IFNγ responses, and develop obliterative airway inflammation and acute transplant rejection. Our results indicate that T-bet/STAT6 DKO mice serving as allograft recipient could be utilized as a new viable model to study the roles of IL-17 in lung transplantation.

CITATION INFORMATION: Liang F., Chen R., Chen Q., Ochando J., Ding Y., Xu J. T-bet and STAT6 Double Deficiency Favors IL-17 Immunity after Lung Transplantation Am J Transplant. 2017;17 (suppl 3).

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