MARCH 1-mediated MHCII ubiquitination promotes dendritic cell selection of natural regulatory T cells

Membrane-associated RING-CH1 (MARCH1) is an E3 ubiquitin ligase that mediates ubiquitination of MHCII and CD86 in DCs (Matsuki et al., 2007; Baravalle et al., 2011). This ubiquitination induces MHCII and CD86 endocytosis, lysosomal transport, and degradation (Shin et al., 2006; van Niel et al., 2006; Baravalle et al., 2011). The functional role of MARCH1 has been studied mainly in the context of DC maturation and T cell activation or regulation in vitro. When DCs are exposed to maturation stimuli, MARCH1 is rapidly down-regulated (De Gassart et al., 2008; Walseng et al., 2010). This down-regulation leads to an increase in MHCII and CD86 on the DC surface, which enhances the ability of the cell to stimulate antigen-specific T cells (Baravalle et al., 2011). In contrast, when DCs are exposed to the immune suppressive cytokine IL-10, MARCH1 is up-regulated (Tze et al., 2011; Baravalle et al., 2011). This up-regulation results in a reduction of MHCII and CD86 surface levels, and diminishes the DC’s ability to activate T cells (Baravalle et al., 2011). These studies suggest that MARCH1 plays a regulatory role in T cell activation during immune responses. However, the role of MARCH1 at steady state or in vivo is not well understood although a recent study has suggested that MARCH1 might be involved in splenic DC homeostasis (OhmuraHoshino et al., 2009). At steady state, MHCII plays an important role in CD4 T cell development in the thymus (Laufer et al., 1996). Furthermore, MHCII critically impacts the development of natural regulatory T cells (T reg cells), a unique CD4 T cell subset equipped with potent immune suppressive capacity (Hsieh et al., 2012). Co-stimulatory molecules, including CD86, also mediate T reg cell and NKT cell development (Salomon et al., 2000; Williams et al., 2008). Thus, given the function of MARCH1 in controlling MHCII CORRESPONDENCE Jeoung-Sook Shin: jeoung-sook.shin@ucsf.edu