著者

佐竹 敦志

出版者

日本サイトメトリー学会

雑誌

サイトメトリーリサーチ (ISSN:09166920)

巻号頁・発行日

vol.25, no.2, pp.7-13, 2015-10-25 (Released:2017-05-08)

参考文献数

18

---

Strategies to expand regulatory T cells (Treg)s hold therapeutic potential for ameliorating T cell-mediated inflammatory diseases. TCR signaling is partially dispensable for IL-2-induced Treg proliferation, as has been shown recently. In contrast, conventional T cells (Tconv)s require TCR signal activation for their proliferation. Therefore, we can expect that in conjunction with IL-2, pharmacological inhibition of TCR signaling may induce the expansion of Tregs while simultaneously inhibiting Tconv proliferation. We hereby demonstrate that costimulation but not TCR-mediated phospholipase Cγ (PLCγ) activation is required for the IL-2-induced Treg proliferation. Using Cyclosporine A (CSA) to inhibit TCR signaling and rapamycin to suppress costimulatory signaling pathways, we also demonstrate that while both agents attenuated antigen-specific Tconv proliferation, only CSA permitted IL-2-induced Treg expansion. Rapamycin, however, did increase the Treg:Tconv ratio due to its negative effects on Tconv survival. Importantly, CSA synergized with IL-2 in protection against experimental autoimmune encephalomyelitis (EAE). However, CSA abolished whereas rapamycin augmented the beneficial effect of IL-2 in graft-versus-host disease (GVHD). These differences could be potentially explained by the ability of rapamycin to promote inducible Treg generation and to allow TCR-enhanced Treg proliferation, processes that were inhibited by CSA but are important for GVHD protection. Thus, depending on the disease setting, different signaling pathways need to be targeted to increase the Treg:Tconv ratio for treatment of T cellmediated inflammatory disorders.