Lymph node-resident dendritic cells drive TH2 cell development involving MARCH1

Type 2 T helper (TH2) cells are protective against parasitic worm infections but also aggravate allergic inflamma-tion. Although the role of dendritic cells (DCs) in TH2 cell differentiation is well established, the underlying mech-anisms are largely unknown. Here, we show that DC induction of TH2 cells depends on membrane-associated RING-CH-1 (MARCH1) ubiquitin ligase. The pro-TH2 effect of MARCH1 relied on lymph node (LN)-resident DCs, which triggered T cell receptor (TCR) signaling and induced GATA-3 expression from naive CD4+ T cells indepen-dent of tissue-driven migratory DCs. Mice with mutations in the ubiquitin acceptor sites of MHCII and CD86, the two substrates of MARCH1, failed to develop TH2 cells. These findings suggest that TH2 cell development depends on ubiquitin-mediated clearance of antigen-presenting and costimulatory molecules by LN-resident DCs and con-sequent control of TCR signaling.