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 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. 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. We have found that the recycling of MHC-II is inhibited by ubiquitination by the March-I E3 ubiquitin ligase in immature DCs and B cells and we are following up on this observation by attempting to regulate MHC-II recycling in a variety of APC types to examine the importance of this post-translational modification on MHC-II function.MHC-II molecules bind antigenic peptides derived from internalized protein antigens, and any defect in antigen internalization can adversely affect the ability of APCs to function as stimulators of immunity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC009404-23
Application #
9556234
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
23
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Bandola-Simon, Joanna; Roche, Paul A (2018) Dysfunction of antigen processing and presentation by dendritic cells in cancer. Mol Immunol :
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:
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
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
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

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