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Dendritic cells (DCs) are critical for the differentiation and activation of type 2 T helper (Th2) cells, which provide protection from parasitic worm infections, yet also aggravate inflammation as seen in asthma and other allergic diseases. Yet little is known concerning the mechanisms employed by DCs to induce Th2 cells in the draining lymph node (LN) or to sustain activation of the T cells in the tissue during ongoing inflammation. In the lymph node, we show that DC induction of Th2 cells depends on the MARCH1 ubiquitin ligase. This pro-Th2 effect of MARCH1 relied on LN-resident DCs, which triggered T cell receptor (TCR) signalling and induced GATA-3 expression from naïve CD4+ T cells independent of tissue-driven migratory DCs. Mice with mutations in the ubiquitin acceptor sites of the antigen presenting molecule MHCII and costimulatory ligand CD86, the substrates of MARCH1, failed to develop Th2 cells. In the allergen-exposed tissue, we also found that MARCH1 in DCs played an essential role in sustaining effector CD4+ T cells. MARCH1-mediated turnover of MHCII and CD86 restrained exhaustion of effector CD4+ T cells, permissive with the robust proliferation of the T cells and the establishment of allergic inflammation. MARCH1 ablation in mice with established asthma reduced tissue infiltration of disease-associated eosinophils and Th2 cells. Thus, Th2 cell development and function in the lymph node and tissue depend on MARCH1-mediated turnover of antigen presenting and costimulatory molecules by DCs to control TCR signalling and T cell exhaustion. MARCH1 may serve as a novel therapeutic target in asthma and other allergic diseases.

Dendritic cells (DCs) are critical for the differentiation and activation of type 2 T helper (Th2) cells, which provide protection from parasitic worm infections, yet also aggravate inflammation as seen in asthma and other allergic diseases. Yet little is known concerning the mechanisms employed by DCs to induce Th2 cells in the draining lymph node (LN) or to sustain activation of the T cells in the tissue during ongoing inflammation. In the lymph node, we show that DC induction of Th2 cells depends on the MARCH1 ubiquitin ligase. This pro-Th2 effect of MARCH1 relied on LN-resident DCs, which triggered T cell receptor (TCR) signalling and induced GATA-3 expression from naïve CD4+ T cells independent of tissue-driven migratory DCs. Mice with mutations in the ubiquitin acceptor sites of the antigen presenting molecule MHCII and costimulatory ligand CD86, the substrates of MARCH1, failed to develop Th2 cells. In the allergen-exposed tissue, we also found that MARCH1 in DCs played an essential role in sustaining effector CD4+ T cells. MARCH1-mediated turnover of MHCII and CD86 restrained exhaustion of effector CD4+ T cells, permissive with the robust proliferation of the T cells and the establishment of allergic inflammation. MARCH1 ablation in mice with established asthma reduced tissue infiltration of disease-associated eosinophils and Th2 cells. Thus, Th2 cell development and function in the lymph node and tissue depend on MARCH1-mediated turnover of antigen presenting and costimulatory molecules by DCs to control TCR signalling and T cell exhaustion. MARCH1 may serve as a novel therapeutic target in asthma and other allergic diseases.