MARCH8 controls thymic epithelial cell MHC II and CD4+ T cell development — ASN Events
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  2. Workshop 5: Lymphocyte biology 2
  3. MARCH8 controls thymic epithelial cell MHC II and CD4+ T cell development

MARCH8 controls thymic epithelial cell MHC II and CD4+ T cell development (#57)

Haiyin Liu 1 , Reema Jain 2 , Daniel Gray 2 , Justine Mintern 1 , Jose Villadangos 1 3
  1. Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC, Australia
  2. Molecular Genetics of Cancer Division and Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  3. Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC, Australia

Recognition of peptide:MHC II complexes on the surface of antigen presenting cells is a critical step in the development and activation of T cells. The expression levels of MHC II are tightly controlled: In dendritic cells and B cells, the E3 ligase Membrane Associated RING-CH 1 (MARCH1) downregulates MHC II via ubiquitination. On the other hand, MHC II is stabilized by the immunoglobulin CD83, which is proposed to sequester MARCH1. Mice that are deficient in CD83 express less surface MHC II on DCs, B cells and thymic epithelial cells (TECs), and their CD4+ T cell numbers are strongly reduced. Unlike in DCs and B cells, MHC II levels are normal in TECs from MARCH1-/- mice, indicating MARCH1 does not regulate MHC II in TECs.

Our studies have identified MARCH8 as the E3 ligase controlling MHC II surface expression in TECs. MHC II surface levels are strongly increased in TECs of MARCH8-/- mice, while MHC II levels on DCs and B cells remain unchanged. Deleting MARCH8 in CD83-deficient restored CD4+ T cell numbers, which implies that MARCH8, not MARCH1, ubiquitinates MHC II in TECs. Remarkably, the increased TEC MHC II levels in MARCH8-/- do not seem to change the T cell repertoire, and even aged MARCH8-/- mice do not show overt signs of autoimmunity.

In summary, our results reveal a novel role for MARCH8 controlling surface MHC II in TECs in a physiological setting, and suggest that limiting MARCH8 activity is critical for the development of CD4+ T cells. Our findings suggest differential control of MHC II trafficking by different antigen presenting cells by way of using different MARCH family ligases.

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