Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Department of Immunology, Harvard Medical School, Boston, MA, USA.
Nat Commun. 2022 Aug 31;13(1):5118. doi: 10.1038/s41467-022-32899-5.
Regulatory T (Treg) cells are central to limit immune responses to allergens. Here we show that PD-L2 deficiency prevents the induction of tolerance to ovalbumin and control of airway hyperreactivity, in particular by limiting pTreg numbers and function. In vitro, PD-1/PD-L2 interactions increase iTreg numbers and stability. In mice lacking PD-L2 we find lower numbers of splenic pTregs at steady state, producing less IL-10 upon activation and with reduced suppressive activity. Remarkably, the numbers of splenic pTregs are restored by adoptively transferring PD-L2 dendritic cells to PD-L2 mice. Functionally, activated pTregs lacking PD-L2 show lower Foxp3 expression, higher methylation of the Treg-Specific Demethylation Region (TSDR) and a decreased Tricarboxylic Acid (TCA) cycle associated with a defect in mitochondrial function and ATP production. Consequently, pyruvate treatment of PD-L2 mice partially restores IL-10 production and airway tolerance. Together, our study highlights the importance of the PD-1/PD-L2 axis in the control of metabolic pathways regulating pTreg Foxp3 stability and suppressive functions, opening up avenues to further improve mucosal immunotherapy.
调节性 T（Treg）细胞对于限制过敏原的免疫反应至关重要。在这里，我们表明 PD-L2 缺乏可防止卵清蛋白诱导的耐受和气道高反应性的控制，特别是通过限制 pTreg 数量和功能。在体外，PD-1/PD-L2 相互作用可增加 iTreg 的数量和稳定性。在缺乏 PD-L2 的小鼠中，我们发现稳态时脾脏 pTreg 的数量较低，在激活时产生较少的 IL-10，并且抑制活性降低。值得注意的是，通过将 PD-L2 树突状细胞过继转移到 PD-L2 小鼠中，可恢复脾脏 pTreg 的数量。功能上，缺乏 PD-L2 的活化 pTreg 显示出较低的 Foxp3 表达，Treg 特异性去甲基化区（TSDR）的甲基化程度更高，三羧酸（TCA）循环减少，与线粒体功能和 ATP 产生缺陷有关。因此，丙酮酸处理 PD-L2 小鼠可部分恢复 IL-10 的产生和气道耐受。总之，我们的研究强调了 PD-1/PD-L2 轴在调节 pTreg Foxp3 稳定性和抑制功能的代谢途径中的重要性，为进一步改善粘膜免疫治疗开辟了途径。
