Anandasabapathy Niroshana, Feder Rachel, Mollah Shamim, Tse Sze-Wah, Longhi Maria Paula, Mehandru Saurabh, Matos Ines, Cheong Cheolho, Ruane Darren, Brane Lucas, Teixeira Angela, Dobrin Joseph, Mizenina Olga, Park Chae Gyu, Meredith Matthew, Clausen Björn E, Nussenzweig Michel C, Steinman Ralph M
Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Department of Dermatology/Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, MA 02115
Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
J Exp Med. 2014 Aug 25;211(9):1875-91. doi: 10.1084/jem.20131397. Epub 2014 Aug 18.
DCs are critical for initiating immunity. The current paradigm in vaccine biology is that DCs migrating from peripheral tissue and classical lymphoid-resident DCs (cDCs) cooperate in the draining LNs to initiate priming and proliferation of T cells. Here, we observe subcutaneous immunity is Fms-like tyrosine kinase 3 ligand (Flt3L) dependent. Flt3L is rapidly secreted after immunization; Flt3 deletion reduces T cell responses by 50%. Flt3L enhances global T cell and humoral immunity as well as both the numbers and antigen capture capacity of migratory DCs (migDCs) and LN-resident cDCs. Surprisingly, however, we find immunity is controlled by cDCs and actively tempered in vivo by migDCs. Deletion of Langerin(+) DC or blockade of DC migration improves immunity. Consistent with an immune-regulatory role, transcriptomic analyses reveals different skin migDC subsets in both mouse and human cluster together, and share immune-suppressing gene expression and regulatory pathways. These data reveal that protective immunity to protein vaccines is controlled by Flt3L-dependent, LN-resident cDCs.
树突状细胞（DCs）对于启动免疫反应至关重要。疫苗生物学的当前范式是，从外周组织迁移而来的DCs与经典的驻留于淋巴组织的DCs（cDCs）在引流淋巴结中协同作用，以启动T细胞的致敏和增殖。在此，我们观察到皮下免疫反应依赖于Fms样酪氨酸激酶3配体（Flt3L）。免疫接种后Flt3L迅速分泌；Flt3缺失使T细胞反应降低50%。Flt3L增强了整体T细胞和体液免疫，以及迁移性DCs（migDCs）和驻留于淋巴结的cDCs的数量和抗原捕获能力。然而，令人惊讶的是，我们发现免疫反应由cDCs控制，且在体内由migDCs积极调节。缺失朗格汉斯蛋白（Langerin）阳性DC或阻断DC迁移可增强免疫反应。与免疫调节作用一致，转录组分析显示，小鼠和人类的不同皮肤migDC亚群聚集在一起，并共享免疫抑制基因表达和调节途径。这些数据表明，对蛋白质疫苗的保护性免疫反应由依赖Flt3L的、驻留于淋巴结的cDCs控制。
