Abstract
Regulatory T-cells (Tregs) play a pivotal role in maintaining peripheral tolerance. Increasing Treg numbers/functions has been shown to ameliorate autoimmune diseases. However, common Treg expansion approaches use T-Cell Receptor (TCR)-mediated stimulation which also causes proliferation of effector T-cells (Teff). To overcome this limitation, purified patient-specific Tregs are expanded ex vivo and transfused. Although promising, this approach is not suitable for routine clinical use. Therefore, an alternative approach to selectively expand functional Tregs in vivo is highly desired. We report a novel TCR-independent strategy for the selective proliferation of Foxp3+Tregs (without Teff proliferation), by co-culturing CD4+ T-cells with OX40 L+Jagged(JAG)-1+ bone marrow-derived DCs differentiated with GM-CSF or treating them with soluble OX40 L and JAG1 in the presence of exogenous IL-2. Tregs expanded using soluble OX40 L and JAG1 were of suppressive phenotype and delayed the onset of diabetes in NOD mice. Ligation of OX40 L and JAG1 with their cognate-receptors OX40 and Notch3, preferentially expressed on Tregs but not on Teff cells, was required for selective Treg proliferation. Soluble OX40L-JAG1-induced NF-κB activation as well as IL-2-induced STAT5 activation were essential for the proliferation of Tregs with sustained Foxp3 expression. Altogether, these findings demonstrate the utility of soluble OX40 L and JAG1 to induce TCR-independent Treg proliferation.
Highlights
Tregs differ from Tconv cells in several aspects including their activation, proliferation and function
G-BMDCs-induced Treg proliferation is mediated through OX40L-JAG1 co-signaling in NOD mice and soluble OX40L-JAG1 are sufficient to cause Treg proliferation in the presence of IL-2
To determine whether OX40 L and JAG1 co-signaling is involved in this G-BMDCs induced Treg proliferation, we pre-treated G-BMDCs with blocking antibodies against OX40 L, JAG1, neurolpilin and ligand for glucocorticoid-induced TNFR family related protein (GITRL) and co-cultured with total CD4+ T-cells
Summary
Tregs differ from Tconv cells in several aspects including their activation, proliferation and function. Tregs can suppress Teff function irrespective of their antigen specificity as well[21,22]. We and others have previously shown that Foxp3+ Treg proliferation, independent of TCR stimulation, can be induced by co-culturing them with a particular subset of dendritic cells (DCs)[23,24,25,26,27,28]. Bone marrow (BM) precursor cells differentiated in the presence of GM-CSF (G-BMDCs), upon co-culture with CD4+ T-cells, caused Treg proliferation mediated through OX40L-JAG1 co-signaling[23]. Unlike TCR-stimulation approach, OX40L-JAG1 caused selective proliferation of Tregs with little or no proliferation of Teff cells. Signaling studies revealed that NF-κB activation induced by OX40L-OX40 and JAG1-Notch[3] interactions, and STAT5 induced by IL-2, were essential for Treg proliferation with sustained Foxp[3] expression. We report a novel “TCR-independent” strategy for the selective expansion of functional Tregs which could have therapeutic implications in various autoimmune diseases including T1D
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