Background. Regulatory T (Treg) cells are with potential to induce transplant tolerance. However, the molecular mechanism of the extrathymic generation of adaptive CD4+Foxp3+ regulatory T (iTreg) cells remains incompletely defined.
Methods. C57BL/6 (B6), IL-2KO, Rag1KO, Foxp3/GFP, and dnTGFBRII mice were purchased from the Jackson laboratory (Bar Harbor, ME). A two-step model was used to dissect the mechanism of iTreg differentiation.
Results. During the initial "conditioning" step, CD4+CD25−Foxp3− naÏve T cells were activated by TCR stimulation. Inhibition of IL-2 signaling via Jak3-Stat5 was required during this step to generate CD4+CD25+Foxp3− cells containing iTreg cell precursors. During the subsequent Foxp3- induction step driven by cytokines, IL-2 was the most potent cytokine to induce Foxp3 expression in these iTreg cell precursors.
This two-step method generated a large number of iTreg cells with relatively stable expression of Foxp3, which were able to prevent CD4+CD45RBhigh cell mediated colitis in Rag1KO mice.
Conclusion. while initial inhibition of IL-2/Stat5 signaling upon T cell priming generates iTreg cell precursors, subsequent activation of IL2/Stat5 signaling in these precursors induces the expression of Foxp3. These findings advance the understanding of iTreg cell differentiation, and may facilitate the therapeutic use of iTreg cells in immune disorders.
To cite this abstract in AMA style:Guo Z, Miyahara Y, Wang G, Khattar M, Schroder P, He X, Chen W, Stepkowski S. Dynamic Dual Role of IL-2 Signaling in the Two-Step Differentiation Process of Adaptive Regulatory T Cells, A [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/dynamic-dual-role-of-il-2-signaling-in-the-two-step-differentiation-process-of-adaptive-regulatory-t-cells-a/. Accessed December 7, 2019.
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