西亚试剂：Functional Regulatory T Cells Produced by Inhibiting Cyclic

发布时间：2025-06-24

Functional Regulatory T Cells Produced by Inhibiting Cyclic Nucleotide Phosphodiesterase Type 3 Prevent Allograft Rejection

Feng, Gang; Nadig, Satish N.; B?ckdahl, Liselotte; Beck, Stephan; Francis, Ross S.; Schiopu, Alexandru; Whatcott, Andrew; Wood, Kathryn J.; Bushell, Andrew

Regulatory T cells (Tregs) manipulated ex vivo have potential as cellular therapeutics in autoimmunity and transplantation. Although it is possibleto expand naturally occurring Tregs, an attractive alternative possibility, particularly suited to solid organ and bone marrow transplantation, is the stimulationof total T cell populations with defined allogeneic antigen-presenting cells (APCs) under conditions that lead to the generationor expansion of donor-reactive, adaptive Tregs. Here we demonstrate that stimulation of mouse CD4+ T cells by immature allogeneic dendritic cells combined with pharmacological inhibition of phosphodiesterase 3 (PDE) resultedin a functional enrichment of Foxp3+ T cells. Without further manipulation or selection, the resultant population delayed skin allograft rejection mediated bypolyclonal CD4+ effectors or donor-reactive CD8+ T cell receptor transgenic T cells and inhibited both effector cell proliferation and T cell priming for interferon-γ production.Notably, PDE inhibition also enhanced the enrichment of human Foxp3+ CD4+ T cells driven by allogeneic APCs. These cells inhibited T cell proliferation in a standard in vitro mixed lymphocyte assayand, moreover, attenuated the development of vasculopathy mediated by autologous peripheral blood mononuclear cells in a functionallyrelevant humanized mouse transplant model. These data establish a method for the ex vivo generation of graft-reactive, functionalmouse and human Tregs that uses a clinically approved agent, making pharmacological PDE inhibition a potential strategy for Treg-based therapies.

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