State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
Immunology. 2021 Sep;164(1):148-160. doi: 10.1111/imm.13350. Epub 2021 Jun 2.
CD11c is a canonical dendritic cell (DC) marker with poorly defined functions in the immune system. Here, we found that blocking CD11c on human peripheral blood mononuclear cell-derived DCs (MoDCs) inhibited the proliferation of CD4 T cells and the differentiation into IFN-γ-producing T helper 1 (Th1) cells, which were critical in acute graft-versus-host disease (aGVHD) pathogenesis. Using allogeneic bone marrow transplantation (allo-BMT) murine models, we consistently found that CD11c-deficient recipient mice had alleviated aGVHD symptoms for the decreased IFN-γ-expressing CD4 Th1 cells and CD8 T cells. Transcriptional analysis showed that CD11c participated in several immune regulation functions including maintaining antigen presentation of APCs. CD11c-deficient bone marrow-derived DCs (BMDCs) impaired the antigen presentation function in coculture assay. Mechanistically, CD11c interacted with MHCII and Hsp90 and participated in the phosphorylation of Akt and Erk1/2 in DCs after multiple inflammatory stimulations. Therefore, CD11c played crucial roles in triggering aGVHD and might serve as a potential target for the prevention and treatment of aGVHD.
CD11c 是一种经典的树突状细胞（DC）标志物，其在免疫系统中的功能尚未明确。在这里，我们发现阻断人外周血单核细胞来源的树突状细胞（MoDC）上的 CD11c 抑制了 CD4 T 细胞的增殖和向产生 IFN-γ的辅助性 T 细胞 1（Th1）分化，而这些在急性移植物抗宿主病（aGVHD）发病机制中至关重要。使用同种异体骨髓移植（allo-BMT）小鼠模型，我们一致发现 CD11c 缺陷型受体小鼠的 aGVHD 症状减轻，因为 IFN-γ表达的 CD4 Th1 细胞和 CD8 T 细胞减少。转录分析表明，CD11c 参与了几种免疫调节功能，包括维持 APC 的抗原呈递。在共培养试验中，CD11c 缺陷型骨髓来源的树突状细胞（BMDC）损害了抗原呈递功能。在机制上，CD11c 与 MHCII 和 Hsp90 相互作用，并在 DC 受到多种炎症刺激后参与 Akt 和 Erk1/2 的磷酸化。因此，CD11c 在引发 aGVHD 中起着至关重要的作用，可能成为预防和治疗 aGVHD 的潜在靶点。
