Regulation of MHC Class II Trafficking in Antigen Presenting Cells

Division Of Basic Sciences - Nci

Investigators

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Abstract

Our lab studies the cell biology of antigen processing and presentation by MHC-I and MHC-II proteins to CD8 and CD4 T cells, respectively. We have re-examined the importance of MHC-I in recycling endosomes for antigen cross-presentation to CD8 T cells. High-resolution STED microscopy has revealed that very little MHC-I is present in recycling endosomes; the majority of intracellular MHC-I is in the trans-Golgi network en route to the plasma membrane. We are also examining the kinetics of MHC-I endocytosis, recycling, and degradation to determine whether newly-synthesized or recycling MHC-I is important for antigen cross-presentation. MHC-II turnover in resting DCs is regulated by the E3 ubiquitin ligase March-I. We have generated mice in which an epitope-tag was appended onto the March-I protein, allowing us to simultaneously follow the kinetics of March-I expression, MHC-II ubiquitination, and MHC-II turnover in DCs and B cells. We found that March-I is a short-lived protein, that March-I transcription and protein expression are rapidly downregulated by APC activation, and that CD83, a known regulator of March-I function, suppresses March-I activity without affecting March-I protein expression.