While Th1, Th2 and Th17 cells are thought to be major effector cells in adaptive alloimmune responses, their respective contribution to allograft rejection remains unclear. Here, we explored the distinct alloreactive role of each subset in an experimental transplant setting by studying T cells from B6.RORΓt knockout (KO) mice (non-Th17, prone to Th1), B6.T-bet KO mice (T-bet-/-, prone to Th2/Th17 differentiation), and B6.RORyt-T-bet double-KO mice (RORΓtgfp/gfpT-bet-/-, prone to Th2 differentiation) in a fully mismatched alloresponse in vivo. T cells recovered from these mouse strains and wt controls were adoptively transferred to B6.RagΓc-/- recipients of fully mismatched Balb/c heart allografts.
Importantly, T cells deficient for T-bet (Th2/Th17 prone) rejected heart allografts at a more accelerated rate (19.8±6.47d) than cells from RORΓtgfp/gfp (Th1 prone) mice (>80d in 63% of mice), indicating a predominance of Th17- over Th1-driven alloimmunity. Unexpectedly, double-deficiency for T-bet and RORΓt (Th2 prone) resulted in early allograft rejection (22.8±3.65d) featuring eosinophilic granulocyte infiltration; T cells from these mice generally showed a Th2-related cytokine profile (by flow cytometry), and a significantly upregulated intragraft mRNA expression of the Th2 related cytokines IL-4, IL-5 and IL-13, and of the transcription factor GATA-3.
Next, we confirmed the importance of Th2-mediated alloreactivity by showing that IL-4 neutralization (with anti-IL-4 blocking antibody) significantly prolongs allograft survival (>60d in 57% of mice) in recipients given RORΓtgfp/gfpT-bet-/- T cells (Th2 prone); consistent with our observation, infiltrating eosinophilic granulocytes were few in these allografts.
We conclude that while Th17 cells predictably promote allograft rejection in T-bet deficiency, Th2 cells which are generally thought to protect allogeneic transplants, may act as potent facilitators of organ transplant rejection in the absence of T-bet and RORΓt.
To cite this abstract in AMA style:Sabet-Baktach M, Rovira J, Farkas S, Eggenhofer E, Lantow M, Koehl G, Dahlke M, Schlitt H, Geissler E, Kroemer A. Double-Deficiency for RORγt and T-Bet Drives Th2-Mediated Allograft Rejection in Mice [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/double-deficiency-for-rort-and-t-bet-drives-th2-mediated-allograft-rejection-in-mice/. Accessed August 10, 2020.
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