Regulation of MHC Class II Trafficking in Antigen Presenting Cells

Division Of Basic Sciences - Nci

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Abstract

In the past year we have specifically investigated how MHC-II gains access to endosomal antigen processing compartments for antigenic peptide binding. We found that endocytosis of MHC-II leads to delivery of MHC-II to both early and late endosomes and that in these compartments internalized MHC-II can bind antigenic peptides and the recycle back to the surface for antigen presentation to T cells. The pathway from early endosomes to the cell surface is controlled by the GTPase Rab11a. We were able to show these different recycling pathways are functionally important, as each pathway is active upon influenza virus uptake into antigen presenting cells. We are also investigating the molecular machinery that regulates the turnover of MHC-II in antigen presenting cells. MHC-II is ubiquitinated by the E3 ubiquitin ligase March-I that diverts internalizing MHC-II from a (default) recycling pathway to a pathway of lysosomal degradation. Using March-I deficient mice we have shown that despite high level expression of MHC-II, antigen presenting cells are defective in March-I deficient mice. Identical defects were found in mutant mice lacking the sole ubiquitination site on MHC-II. RNA Sequence analysis revealed that dendritic cells isolated from either ubiquitination-deficient mouse are developmentally altered, explaining their diminished function. We also found that activation of these cells corrects their functional defect and RNA Sequence analysis confirmed that activated mutant and wild-type dendritic cells have identical gene expression profiles.