MHC class II (MHC II) molecules associate with a chaperone protein termed the Invariant chain (Ii) that facilitates the transport of newly synthesized MHC-II to endo/lysosomal antigen processing compartments. Expression of Ii is required for APCs to stimulate most, but certainly not all, antigen-specific T cells. It is thought that these Ii-independent antigens are presented by pre-existing peptide-loaded MHC-II (pMHC-II) that internalize from the plasma membrane, enter into endosomal compartments, exchange old peptides for new antigenic peptides, and then recycle back to the plasma membrane for presentation to CD4 T cells. We have recently shown that unlike Ii-associated MHC-II, pre-existing pMHC-II on the plasma membrane rapidly internalizes into APCs and is returned to the plasma membrane following an Arf6, Rab35, and EHD1-dependent recycling pathway, thereby revealing the molecular machinery responsible for pMHC-II recycling in APCs. In most APCs, the endo/lysosomal antigen processing compartments have properties of multivesicular bodies (MVBs). MVBs are formed by the invagination of the limiting membrane of the organelle, giving rise to a 500 nm structure filled with 50-100 nm vesicles. Curiously, MHC-II is present primarily on the intralumenal vesicles of MVB and it is thought that the sorting of MHC-II into these intralumenal vesicles is essential for proper MHC-II-peptide loading. The sorting signals that direct MHC-II onto the intralumenal vesicles of MVB have not been identified, and we will identify these signals and determine the extent to which specific recognition proteins (such as ESCRT), lipids (such as cholesterol or lysobisphosphatidic acid, LBPA), or post-translational modifications of MHC-II (such as ubiquitination) regulate MHC-II entry and/or exit from these compartments for antigen loading.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC009404-17
Application #
8348935
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2011
Total Cost
$852,802
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Cresswell, Peter; Roche, Paul A (2017) Editorial Overview: Antigen Processing and Presentation; many fingers in many pies. Curr Opin Immunol 46:v-vii
Roche, Paul A; Cresswell, Peter (2016) Antigen Processing and Presentation Mechanisms in Myeloid Cells. Microbiol Spectr 4:
Liu, Zhenzhen; Roche, Paul A (2015) Macropinocytosis in phagocytes: regulation of MHC class-II-restricted antigen presentation in dendritic cells. Front Physiol 6:1
Cho, Kyung-Jin; Walseng, Even; Ishido, Satoshi et al. (2015) Ubiquitination by March-I prevents MHC class II recycling and promotes MHC class II turnover in antigen-presenting cells. Proc Natl Acad Sci U S A 112:10449-54
Anderson, Howard A; Roche, Paul A (2015) MHC class II association with lipid rafts on the antigen presenting cell surface. Biochim Biophys Acta 1853:775-80
Roche, Paul A; Furuta, Kazuyuki (2015) The ins and outs of MHC class II-mediated antigen processing and presentation. Nat Rev Immunol 15:203-16
Mittal, Sharad K; Roche, Paul A (2015) Suppression of antigen presentation by IL-10. Curr Opin Immunol 34:22-7
Cresswell, Peter; Roche, Paul A (2014) Invariant chain-MHC class II complexes: always odd and never invariant. Immunol Cell Biol 92:471-2
Bosch, Berta; Heipertz, Erica L; Drake, James R et al. (2013) Major histocompatibility complex (MHC) class II-peptide complexes arrive at the plasma membrane in cholesterol-rich microclusters. J Biol Chem 288:13236-42
Cho, Kyung-Jin; Roche, Paul A (2013) Regulation of MHC Class II-Peptide Complex Expression by Ubiquitination. Front Immunol 4:369

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