Double Deficiency for ROR gamma t and T-bet Drives Th2-Mediated Allograft Rejection in Mice

作者：Sabet Baktach Manije; Eggenhofer Elke; Rovira Jordi; Renner Philipp; Lantow Margareta; Farkas Stefan A; Malaise Muriel; Edtinger Karoline; Zhou Shaotang; Koehl Gudrun E; Dahlke Marc H; Schlitt Hans J; Geissler Edward K; Kroemer Alexander^*

来源：The Journal of Immunology, 2013, 191(8): 4440-4446.

DOI：10.4049/jimmunol.1301741

Although Th1, Th2, and Th17 cells are thought to be major effector cells in adaptive alloimmune responses, their respective contribution to allograft rejection remains unclear. To precisely address this, we used mice genetically modified for the Th1 and Th17 hallmark transcription factors T-bet and ROR gamma t, respectively, which allowed us to study the alloreactive role of each subset in an experimental transplant setting. We found that in a fully mismatched heterotopic mouse heart transplantation model, T cells deficient for T-bet (prone to Th17 differentiation) versus ROR gamma t (prone to Th1 differentiation) rejected allografts at a more accelerated rate, indicating a predominance of Th17- over Th1-driven alloimmunity. Importantly, T cells doubly deficient for both T-bet and ROR gamma t differentiated into alloreactive GATA-3-expressing Th2 cells, which promptly induced allograft rejection characterized by a Th2-type intragraft expression profile and eosinophilic infiltration. Mechanistically, Th2-mediated allograft rejection was contingent on IL-4, as its neutralization significantly prolonged allograft survival by reducing intragraft expression of Th2 effector molecules and eosinophilic allograft infiltration. Moreover, under IL-4 neutralizing conditions, alloreactive double-deficient T cells upregulated Eomesodermin (Eomes) and IFN-gamma , but not GATA-3. Thus, in the absence of T-bet and ROR gamma t, Eomes may salvage Th1-mediated alloimmunity that underlies IL-4 neutralization-resistant allograft rejection. We summarize that, whereas Th17 cells predictably promote allograft rejection, IL-4-producing GATA-(3+) Th2 cells, which are generally thought to protect allogeneic transplants, may actually be potent facilitators of organ transplant rejection in the absence of T-bet and ROR gamma t. Moreover, Eomes may rescue Th1-mediated allograft rejection in the absence of IL-4, T-bet, and ROR gamma t.

• 出版日期2013-10-15