Allogeneic memory T cell response precludes the induction of transplant acceptance; how this process is regulated at the molecular level remains unclear. Both mTOR and STAT3 are important “drivers” for T cell differentiation and function, but they have been shown to play opposing roles in memory T cell development. STAT3 promotes the functional maturation of memory T cells, whereas mTOR activity negatively regulates the magnitude and qualities of memory T cell differentiation. Herein, to determine the role of mTOR and STAT3 in regulating allogenic memory T cell response, we generated Mtor^fl/flCD4-Cre, Stat3^fl/flCD4-Cre, and Mtor^fl/flStat3^fl/flCD4-Cre mice, in which mTOR, STAT3, or both mTOR and STAT3 was conditionally knocked out (cKO) in T cells. We then transplanted Balb/c ear skins onto wild type (WT) B6 and those cKO mice (n = 5 or 6 per group). 40-50 days later, all recipient mice were transplanted again with Balb/c hearts. Skin allograft survival (mean ± SD) was 9.5 ± 0.55 days on WT mice, 14.2 ± 1.17 days on mTOR cKO mice, 15.5 ± 0.55 days on STAT3 cKO mice, and 17.0 ± 0.89 days on mTOR/STAT3 cKO mice. Heart allograft survival in donor skin-sensitized WT, mTOR cKO or STAT3 cKO mice was 4.6 ± 0.55, 15.0 ± 12.83, or 19.0 ± 4.18 days, respectively. Strikingly, all donor skin-sensitized mTOR/STAT3 cKO recipients permanently accepted the heart allografts (all > 100 days). Therefore, ablation of either mTOR or STAT3 in T cells prolongs the heart allograft survival in donor skin-sensitized mice, whereas ablation of both mTOR and STAT3 in T cells induces heart transplant acceptance in donor skin-sensitized mice. Taken together, mTOR should not be simply considered as a negative regulator for memory T cell differentiation. Targeting both mTOR and STAT3 pathways may have a great therapeutic potential to eliminate allogeneic memory T cell response.

CITATION INFORMATION: Xie A., Chen W. Ablation of Both mTOR and STAT3 in T Cells Induces Heart Transplant Acceptance in Donor Skin-Sensitized Mice Am J Transplant. 2017;17 (suppl 3).

« Back to 2018 American Transplant Congress