Differential impact of mammalian target of rapamycin inhibition on CD4(+)CD25(+)Foxp3(+) regulatory T cells compared with conventional CD4(+) T cells
ABSTRACT Based on their ability to control T-cell homeostasis, Foxp3(+)CD4(+)CD25(+) regulatory T cells (Tregs) are being considered for treatment of autoimmune disorders and acute graft-versus-host disease (aGVHD). When combining Tregs with the immunosuppressant rapamycin (RAPA), we observed reduced alloreactive conventional T-cell (Tconv) expansion and aGVHD lethality compared with each treatment alone. This synergistic in vivo protection was paralleled by intact expansion of polyclonal Tregs with conserved high FoxP3 expression. In contrast to Tconv, activation of Tregs with alloantigen and interleukin-2 preferentially led to signal transducer and activator of transcription 5 (STAT5) phosphorylation and not phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activity. Expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a negative regulator of the PI3K/Akt/mTOR pathway, remained high in Tregs but not Tconv during stimulation. Conversely, targeted deletion of PTEN increased susceptibility of Tregs to mTOR inhibition by RAPA. Differential impact of RAPA as a result of reduced usage of the mTOR pathway in Tregs compared with conventional T cells explains the synergistic effect of RAPA and Tregs in aGVHD protection, which has important implications for clinical trials using Tregs.
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ABSTRACT: Intramuscular (IM) administration of an adeno-associated viral (AAV) vector represents a simple and safe method of gene transfer for treatment of the X-linked bleeding disorder hemophilia B (factor IX, F.IX, deficiency). However, the approach is hampered by an increased risk of immune responses against F.IX. Previously, we demonstrated that the drug cocktail of immune suppressants rapamycin, IL-10, and a specific peptide (encoding a dominant CD4(+) T cell epitope) caused an induction of regulatory T cells (Treg) with a concomitant apoptosis of antigen-specific effector T cells (Nayak et al., 2009). This protocol was effective in preventing inhibitory antibody formation against human F.IX (hF.IX) in muscle gene transfer to C3H/HeJ hemophilia B mice (with targeted F9 gene deletion). Here, we show that this protocol can also be used to reverse inhibitor formation. IM injection of AAV1-hF.IX vector resulted in inhibitors of on average 8-10 BU within 1 month. Subsequent treatment with the tolerogenic cocktail accomplished a rapid reduction of hF.IX-specific antibodies to <2 BU, which lasted for >4.5 months. Systemic hF.IX expression increased from undetectable to >200 ng/ml, and coagulation times improved. In addition, we developed an alternative prophylactic protocol against inhibitor formation that did not require knowledge of T cell epitopes, consisting of daily oral administration of rapamycin for 1-month combined with frequent, low-dose intravenous injection of hF.IX protein. Experiments in T cell receptor transgenic mice showed that the route and dosing schedule of drug administration substantially affected Treg induction. When combined with intravenous antigen administration, oral delivery of rapamycin had to be performed daily in order to induce Treg, which were suppressive and phenotypically comparable to natural Treg.Frontiers in Microbiology 01/2011; 2:244. DOI:10.3389/fmicb.2011.00244 · 3.94 Impact Factor
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ABSTRACT: In the two-signal model of T cell activation, the outcome of antigen recognition is determined by the integration of multiple cues in the immune microenvironment. mTOR is an evolutionarily conserved PI3-kinase family member that plays a central role in integrating environmental cues in the form of amino acids, energy, and growth factors. Recently, an increasingly important role for mTOR in directing T cell activation and differentiation has become apparent. Here we review recent findings demonstrating the ability of mTOR to interpret signals in the immune microenvironment and program the generation of CD4(+) effector versus regulatory T cells, the generation of CD8(+) effector versus memory cells, T cell trafficking, and T cell activation versus anergy. The key theme to emerge from these studies is that the central role of mTOR provides a direct link between T cell metabolism and function.Immunity 09/2010; 33(3):301-11. DOI:10.1016/j.immuni.2010.09.002 · 19.75 Impact Factor
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ABSTRACT: PURPOSE OF REVIEW: Solid organ transplantation is the most effective treatment for end-stage organ failure, but the long-term outcomes remain suboptimal. CD4 regulatory T cells (Tregs) are emerging as a potential therapy to facilitate long-term allograft survival. This review provides a general overview of the biology of CD4 Tregs and then goes on to discuss the most relevant and recent experimental and clinical evidence for their therapeutic use in solid organ transplantation. RECENT FINDINGS: There have been major advances in our understanding of Tregs, including improvements in methods for their isolation and expansion. Experimental models are providing very important data on the in-vitro and in-vivo behavior of Tregs in transplantation, while recent clinical trials of Treg cellular therapy in graft-versus-host disease are offering a valuable insight into the efficacy of Treg adoptive cellular therapy. SUMMARY: Data in favor of Treg cellular therapy in transplantation are mounting, and we predict that their use in clinical trials is on the horizon.Current opinion in organ transplantation 09/2010; 15(6). DOI:10.1097/MOT.0b013e32834017ae · 2.38 Impact Factor