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DEPTOR Inhibits mTORC1 in CD4+ T Cells and Increases Treg Function by Stabilizing Foxp3 Expression.

J. Wedel,1,2 S. Bruneau,1,2 D. Briscoe.1,2

1Division of Nephrology, Boston Children's Hospital, Boston, MA
2Transplant Research Program, Harvard Medical School, Boston, MA.

Meeting: 2016 American Transplant Congress

Abstract number: 252

Keywords: Rejection, T cells

Session Information

Date: Monday, June 13, 2016

Session Name: Concurrent Session: Regulatory T Cells: Animal Models

Session Time: 2:30pm-4:00pm

 Presentation Time: 3:18pm-3:30pm

Location: Room 309

Related Abstracts
  • Novel Function of CD4+ T Cell DEPTOR in Treg Homeostasis and Alloimmunity.
  • DEPTOR Is Expressed in CD4+ T Cells and Modulates Effector Responses and Allograft Rejection

The modulation of PI-3K/Akt-induced signaling is critical for CD4+ Treg homeostasis and stability. Moreover, activation of PI-3K/Akt/mTOR signals within T cell subsets is associated with enhanced Teff cell activity. DEPTOR is a recently discovered mTOR-binding partner and a negative regulator of the Akt/mTOR signaling pathway. However, its expression and function in T cell activation and alloimmunity is unexplored.

By qPCR, Western blot analysis and immunofluorescence, we find high levels of DEPTOR expression in CD4+ T cells, and further we observed that its expression levels were reduced at early times (<3h) following mitogen activation. We harvested CD4+ T cells from a doxycycline (dox)-inducible DEPTOR transgenic mouse (rtTA+/+DEPTOR+/+, iDEP) to evaluate the effect of DEPTOR overexpression on Teff/Treg responses. Treatment of iDEP CD4+ T cells with dox (0.3-3 mcg/ml) resulted in a marked induction of DEPTOR, and this effect was associated with reduced expression of pS6K and induced expression of pAkt(S473). We also cultured naive CD4+CD25– iDEP cells in standard iTreg-inducing media (anti-CD3/anti-CD28, TGF-β, IL-2 and retinoic acid) ± dox (3 mcg/ml). We observed that ~80% of the iDEP cells expressed Foxp3 and the addition of dox into cultures (to force DEPTOR expression) had no effect on iTreg differentiation. Nevertheless, in preliminary experiments, dox-treated and DEPTOR-expressing iTregs were more potent to inhibit Teff proliferation in suppression assays in vitro. Also, as expected, dox had no effect on suppressive potential of rapamycin-induced iTreg. We assessed iTreg stability over 7 days by monitoring Foxp3 expression upon restimulation with anti-CD3/anti-CD28. While only 9.9±5.8% of iTreg retained expression of Foxp3 after 7 days of restimulation, the addition of dox (3 mcg/ml to induce DEPTOR) resulted in significantly (p<0.001) higher frequencies of Foxp3+ Tregs (46.1±6.0%).

In summary, our findings identify DEPTOR as a cell intrinsic regulator of the mTOR pathway in CD4+ T cells and as endogenous immunoregulatory protein that stabilizes Foxp3 expression and enhances Treg function in vitro.

CITATION INFORMATION: Wedel J, Bruneau S, Briscoe D. DEPTOR Inhibits mTORC1 in CD4+ T Cells and Increases Treg Function by Stabilizing Foxp3 Expression. Am J Transplant. 2016;16 (suppl 3).

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To cite this abstract in AMA style:

Wedel J, Bruneau S, Briscoe D. DEPTOR Inhibits mTORC1 in CD4+ T Cells and Increases Treg Function by Stabilizing Foxp3 Expression. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/deptor-inhibits-mtorc1-in-cd4-t-cells-and-increases-treg-function-by-stabilizing-foxp3-expression/. Accessed March 4, 2021.

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