Type 2 Immune Development Depends on MARCH1-mediated MHCII and CD86 Turnover in Lymph Node Resident Dendritic Cells Authors: Carlos A. Castellanos (1), Xin Ren (2), Hong-Erh Liang (3), Brian J. Laidlaw (4), Satoshi Ishido (5), Jason G. Cyster (4), Richard M. Locksley (3), Xiaozhu Huang (2), and Jeoung-Sook Shin (1) Affiliations: (1) Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA. (2) Department of Medicine, Lung Biology Center, University of California, San Francisco, San Francisco, CA 94158, USA. (3) Department of Medicine, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA. (4) Department of Microbiology and Immunology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA. (5) Department of Microbiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan. Abstract: Th2 cells protect host from parasitic worm infection but also aggravate allergic inflammatory diseases including asthma. The role of dendritic cells (DCs) in Th2 cell development is well established, yet underlying mechanisms are unclear. We found that development of Th2 cells by DCs depends on membrane-associated RING-CH1 (MARCH1), an E3 ligase that mediates ubiquitination and endolysosomal degradation of MHCII and CD86. Mice lacking MARCH1 in DCs failed to develop Th2 cells against environmental allergens and parasitic worms although they remained competent at developing Th1 and cytotoxic T cells against influenza. While Th2 cell development often associates with DC migration to the draining lymph node, MARCH1 was barely expressed in migratory DCs, and the effect of MARCH1 in promoting Th2 cell development was not dependent on migratory DCs. Moreover, a DC migration blockade did not impair the expression of GATA3 in developing Th2 cells in the lymph node while MARCH1 deficiency did, suggesting MARCH1 promotes Th2 cell development through its expression in the lymph node-resident DCs. MARCH1 deficiency resulted in 7-10 fold increase in MHCII and CD86 in the lymph node-resident DCs. Mice with mutations in the ubiquitin acceptor amino acids of MHCII and CD86 also showed marked accumulation of these molecules in the lymph node-resident DCs and exhibited poor induction of GATA3 in developing Th2 cells and poor Th2 cell inflammation in allergen-exposed airway. Thus, development of Th2 cell immunity depends on ubiquitin-mediated control of antigen presenting and costimulatory molecules in lymph node-resident DCs.