Introduction: Transcription factors essential for pathogenic Th1 and Th2 development have been shown to regulate some aspects of Treg functions during inflammation and autoimmunity. We hypothesized that Th1 and Th2 transcription factors regulate Treg migration and protective function for graft survival.

Methods: BALB/c islets were transplanted underneath the kidney capsule of streptozotocin-induced diabetic C57BL/6 recipients. For adoptive transfers, 1×10⁶ CD4⁺CD25⁺ Treg cells were isolated from C57BL/6 wild type (WT), T-bet KO (Th1 transcription factor), Stat6 KO (Th2 transcription factor), or T-bet/Stat6 DKO mice (all C57BL/6 background) and were transferred either intravenously, or locally together with islets, at the time of transplantation. Allograft function was monitored by blood glucose.

Results: Untreated recipients rejected the islets acutely (median survival time, MST = 10 days). WT Treg significantly prolonged graft survival when administered intravenously (MST 30d) and more so when administered locally (MST 39d). T-bet KO Treg prolonged graft survival by only a few days when transferred either iv (MST 15d) or locally (MST 18d). Stat6 KO Treg failed to prolong graft survival when transferred locally (MST 13d), but modestly prolonged graft survival when transferred locally (MST 16d). T-bet/Stat6 DKO prolonged survival a few days when transferred iv (MST 14d), and were significantly more effective when transferred locally (MST 22d). The expression of Foxp3 in CD4⁺CD25⁺ T cells were similar in all strains, and all had similar in vitro suppressive effector properties.

Conclusions: Both Th1 and Th2 transcription factors are essential in the suppressive function of Treg for prolongation of islet allograft survival. Th1 and Th2 transcription factors do not balance one another, since the combined DKO was equally impaired in its ability to prolong graft survival. Therapies which have been directly against Th1 and Th2 pathways have likely failed in the past due to unintended consequences on Treg function and migration.

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