MARCH1 ubiquitin ligase rescues thymic dendritic cells from MHCII proteotoxicity and supports regulatory T cell development and repertoire expansion

Membrane-Associated RING-CH1 (MARCH1) is an ubiquitin ligase preferentially expressed in antigen-presenting cells and mediating ubiquitination and degradation of MHCII and CD86. MARCH1 deficiency results in a significant reduction in the number of thymic regulatory T (Treg) cells in mice, implicating an important role of this molecule in Treg cell development. However, neither the mechanism by which MARCH1 supports Treg cell development nor its impact on Treg cell function has been clearly defined. Here we report that the role of MARCH1 in Treg cell development critically depends on its expression in dendritic cells and its activity to ubiquitinate MHCII. Importantly, not the MHCII ubiquitination per se but its consequences to MHCII proteostasis is essential for dendritic cells to organize surface proteins appropriately, make a stable conjugate with thymocytes, and provide them with sufficient signal for Treg cell differentiation. When MARCH1-mediated MHCII proteostasis in dendritic cells fails, Treg cells develop to a markedly reduced number and a substantially restricted TCR repertoire in the thymus, resulting in the function of these cells to suppress graft-versus-host-disease severely impaired. Thus, MARCH1-mediated MHCII proteostasis plays an essential role for thymic dendritic cells to select regulatory T cells in abundance and diversity required for proper immune suppression.