Abstract

Abstract 2158Regulatory T cells (Tregs) are suppressive T cells with therapeutic potential for ameliorating T cell-mediated diseases. Thus, there has been great interest in revealing the mechanisms by which Tregs proliferate. Recently, we reported that TCR signaling is partially dispensable for Treg proliferation in vivo when exogenous IL-2 is administered. Based on this data, we hypothesized that when given in conjunction with IL-2, pharmacological inhibition of TCR signaling might allow Tregs to expand while simultaneously inhibiting conventional T cell (Tconv) proliferation.Using mutant mice with defective TCR-mediated PLCγ activation, we found that the activation of PLCγ is dispensable for IL-2-mediated Treg proliferation. In contrast, costimulation-derived mTOR signaling was required for IL-2-induced Treg proliferation. We next used Cyclosporine A (CSA; calcineurin inhibitor) and rapamycin (mTOR inhibitor) to differentially target these signaling pathways. Consistent with our hypothesis, while both CSA and rapamycin suppressed antigen-specific Tconv proliferation, only CSA permitted IL-2-induced Treg expansion in vitro and in vivo. Rapamycin, however, did increase the overall Treg:Tconv ratio due to its negative effects on Tconv survival.Given that CSA inhibited antigen-specific Tconv proliferation while maintaining IL-2-induced Treg expansion, we hypothesized that the combination of CSA and IL-2 would be beneficial for attenuating T cell-mediated disease. Indeed, CSA synergized with IL-2 in protection against experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Surprisingly, however, the administration of CSA blocked whereas rapamycin augmented the beneficial effect of IL-2 in graft-versus-host disease (GVHD). These differences potentially results from the overt TCR stimulation that Tregs would receive in the allogeneic (GVHD) vs. syngeneic (EAE) environment. Moreover, inducible Treg (iTreg) generation from allogeneic MHC-stimulated naïve Tconvs contributes greatly to the Treg pool during GVHD. This was consistent with our data showing that rapamycin promotes iTreg generation and allows TCR-enhanced Treg proliferation, whereas CSA inhibited both of these processes. Thus, depending on the disease setting, the signaling pathways contributing to expansion of the Treg pool need to be carefully considered and specifically targeted to increase the Treg:Tconv ratio in treatment of T cell-mediated disorders. Disclosures:No relevant conflicts of interest to declare.

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.