Zhu Jingru, Wang Yitong, Li Jingxia, Das Pankoj Kumar, Zhang Hanwen, Passang Tenzin, Li Jian Ming, Nagy Tamas, Gandhi Khanjan, Ravindranathan Sruthi, Giver Cynthia R, Hassan Mojibade, Li Yiwen, Antonova Alina Ulezko, Wang Shuhua, Roback John D, Waller Edmund K
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA.
Department of Oncology, Xiangya Hospital, Central South University (CSU), Changsha, People's Republic of China.
Blood. 2022 Sep 22;140(12):1431-1447. doi: 10.1182/blood.2021012561.
Vasoactive intestinal polypeptide (VIP), an anti-inflammatory neuropeptide with pleiotropic cardiovascular effects, induces differentiation of hematopoietic stem cells into regulatory dendritic cells that limit graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplant (HSCT) recipients. We have previously shown that donor plasmacytoid dendritic cells (pDCs) in bone marrow (BM) donor grafts limit the pathogenesis of GVHD. In this current study we show that murine and human pDCs express VIP, and that VIP-expressing pDCs limit T-cell activation and expansion using both in vivo and in vitro model systems. Using T cells or pDCs from transgenic luciferase+ donors in murine bone marrow transplantation (BMT), we show similar homing patterns of donor pDCs and T cells to the major sites for alloactivation of donor T cells: spleen and gut. Cotransplanting VIP-knockout (KO) pDCs with hematopoietic stem cells and T cells in major histocompatibility complex mismatched allogeneic BMT led to lower survival, higher GVHD scores, and more colon crypt cell apoptosis than transplanting wild-type pDCs. BMT recipients of VIP-KO pDCs had more T helper 1 polarized T cells, and higher plasma levels of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-α than recipients of wild-type pDCs. T cells from VIP-KO pDC recipients had increasing levels of bhlhe40 transcripts during the first 2 weeks posttransplant, and higher levels of CyclophilinA/Ppia transcripts at day 15 compared with T cells from recipients of wild-type pDCs. Collectively, these data indicate paracrine VIP synthesis by donor pDCs limits pathogenic T-cell inflammation, supporting a novel mechanism by which donor immune cells regulate T-cell activation and GVHD in allogeneic BMT.
血管活性肠肽（VIP）是一种具有多效心血管作用的抗炎神经肽，可诱导造血干细胞分化为调节性树突状细胞，从而限制异基因造血干细胞移植（HSCT）受者的移植物抗宿主病（GVHD）。我们之前已经表明，骨髓（BM）供体移植物中的供体浆细胞样树突状细胞（pDC）可限制GVHD的发病机制。在本研究中，我们发现小鼠和人类pDC表达VIP，并且表达VIP的pDC使用体内和体外模型系统限制T细胞的激活和扩增。在小鼠骨髓移植（BMT）中，使用来自转基因荧光素酶+供体的T细胞或pDC，我们发现供体pDC和T细胞归巢到供体T细胞同种异体激活的主要部位（脾脏和肠道）的模式相似。在主要组织相容性复合体不匹配的异基因BMT中，将VIP基因敲除（KO）的pDC与造血干细胞和T细胞共移植，与移植野生型pDC相比，导致更低的存活率、更高的GVHD评分和更多的结肠隐窝细胞凋亡。VIP-KO pDC的BMT受者比野生型pDC的受者有更多的T辅助1极化T细胞，以及更高水平的粒细胞-巨噬细胞集落刺激因子和肿瘤坏死因子-α。与野生型pDC受者的T细胞相比，VIP-KO pDC受者的T细胞在移植后前2周内bhlhe40转录本水平升高，在第15天CyclophilinA/Ppia转录本水平更高。总体而言，这些数据表明供体pDC的旁分泌VIP合成限制了致病性T细胞炎症，支持了一种新的机制，即供体免疫细胞在异基因BMT中调节T细胞激活和GVHD。
