Hongo D, Tang X, Baker J, Engleman E G, Strober S
Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA.
Am J Transplant. 2014 Nov;14(11):2467-77. doi: 10.1111/ajt.12914. Epub 2014 Oct 13.
The goal of the study was to elucidate the cellular and molecular mechanisms by which a clinically applicable immune tolerance regimen of combined bone marrow and heart transplants in mice results in mixed chimerism and graft acceptance. The conditioning regimen of lymphoid irradiation and anti-T cell antibodies changed the balance of cells in the lymphoid tissues to create a tolerogenic microenvironment favoring the increase of natural killer T (NKT) cells, CD4+ CD25+ regulatory T cells and Gr-1+ CD11b+ myeloid-derived suppressor cells (MDSCs), over conventional T cells (Tcons). The depletion of MDSCs abrogated chimerism and tolerance, and add back of these purified cells was restorative. The conditioning regimen activated the MDSCs as judged by the increased expression of arginase-1, IL-4Rα and programmed death ligand 1, and the activated cells gained the capacity to suppress the proliferation of Tcons to alloantigens in the mixed leukocyte reaction. MDSC activation was dependent on the presence of host invariant NKT cells. The conditioning regimen polarized the host invariant NKT cells toward IL-4 secretion, and MDSC activation was dependent on IL-4. In conclusion, there was a requirement for MDSCs for chimerism and tolerance, and their suppressive function was dependent on their interactions with NKT cells and IL-4.
该研究的目的是阐明在小鼠中联合进行骨髓和心脏移植的临床适用免疫耐受方案导致混合嵌合体形成和移植物接受的细胞及分子机制。淋巴照射和抗T细胞抗体的预处理方案改变了淋巴组织中细胞的平衡，从而营造出一种促耐受性微环境，相较于传统T细胞（Tcons），有利于自然杀伤T（NKT）细胞、CD4+ CD25+调节性T细胞和Gr-1+ CD11b+髓源性抑制细胞（MDSCs）数量增加。MDSCs的清除消除了嵌合体形成和耐受性，而回输这些纯化细胞则具有恢复作用。从精氨酸酶-1、IL-4Rα和程序性死亡配体1表达增加可判断，预处理方案激活了MDSCs，且活化后的细胞获得了在混合淋巴细胞反应中抑制Tcons对同种异体抗原增殖的能力。MDSC激活依赖于宿主恒定NKT细胞的存在。预处理方案使宿主恒定NKT细胞向分泌IL-4极化，且MDSC激活依赖于IL-4。总之，嵌合体形成和耐受性需要MDSCs，其抑制功能依赖于它们与NKT细胞及IL-4的相互作用。
