pH-susceptibility of HLA-DO tunes DO/DM ratios to regulate HLA-DM catalytic activity

Jiang, Wei; Strohman, Michael; Somasundaram, Sriram; Ayyangar, Sashi; Hou, Tieying; Wang, Nan; Mellins, Elizabeth

doi:10.1038/srep17333

Cited by 26 publications

(52 citation statements)

References 45 publications

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“…Due to lack of working antibodies for mouse cells, we were not able to analyse H2-O in our system. Nevertheless, H2-O has been shown to dissociate from H2-M in acidic pH, thereby releasing the inhibition of peptide loading by H2-M (Jiang et al, 2015). This mechanism would allow peptide loading already from eMHCII even in the presence of H2-O.…”

Section: Discussionmentioning

confidence: 99%

B cells rapidly target antigen and surface-derived MHCII into peripheral degradative compartments

Hernández-Pérez

Vainio

Kuokkanen

et al. 2019

Preprint

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In order to mount high-affinity antibody responses, B cells internalise specific antigens and process them into peptides loaded onto MHCII for presentation to Th cells. While the biochemical principles of antigen processing and MHCII loading have been well dissected, how the endosomal vesicle system is wired to enable these specific functions remains much less studied. Here, we performed a systematic microscopy-based analysis of antigen trafficking in B cells to reveal its route to the MHCII peptide-loading compartment (MIIC). Surprisingly, we detected fast targeting of internalised antigen into peripheral acidic compartments that possessed the hallmarks of MIIC and also showed degradative capacity. In these vesicles, internalised antigen converged rapidly with membrane-derived MHCII and partially overlapped with Cathepsin-S and H2-M, both required for peptide loading. These early compartments appeared heterogenous and atypical as they contained a mixture of both early and late markers, indicating specialized endosomal route. Together, our data suggests that, in addition to previously-reported perinuclear late endosomal MIICs, antigen processing and peptide loading could start already in these specialized early peripheral acidic vesicles (eMIIC) to support fast peptide-MHCII presentation.

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Section: Discussionmentioning

confidence: 99%

B cells rapidly target antigen and surface-derived MHCII into peripheral degradative compartments

Hernández-Pérez

Vainio

Kuokkanen

et al. 2019

Preprint

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“…Analysis of Epitope Source Protein Intracellular Localization-Because DO has been suggested to control the intracellular location of antigen loading through its effects on DM (26,27,66,67), we evaluated the GO-annotated cellular compartments (68,69) for source proteins from which the eluted peptides were derived. These were not appreciably different between WT and DO-KO, suggesting that the location of antigen loading was not substantially altered by the presence of DO (supplemental Fig.…”

Section: Generation and Validation Of Do-ko And Wt Clones-mentioning

confidence: 99%

HLA-DO Modulates the Diversity of the MHC-II Self-peptidome

Nanaware

Jurewicz

Leszyk

et al. 2019

Molecular & Cellular Proteomics

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In BriefComprehensive analysis of MHC-II immunopeptidomes from cells lacking DO (human HLA-DO or murine H2-O) shows that DO controls the diversity of the MHC-II peptide repertoire. DO expression leads to presentation of a broader distribution of peptides, with many low-abundance epitopes presented only in the presence of DO. We suggest that regulated expression of DO allows the immune system to maintain tolerance to a wide variety of self-antigens and allows for an immune response focused on immunodominant antigens for pathogen recognition. Highlights• MHC-II-bound peptide repertoires from DO-sufficient and DO-deficient cells.• Fewer unique peptides and core epitopes were presented in the absence of DO.• Immunopeptidome differences appeared to result from reduced DM editing.• DO-dependent self-epitopes elicited CD4 T cell responses in mice.

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“…The molecular interaction between intact DO and DM is pH insensitive, even at the lysosomal pH (125). This raises questions as to how DO-associated DM is freed to edit MHCII-associated peptide cargo, and what role DO plays to modulate the B cell MHCII peptidome.…”

Section: Generation Of the Mhcii/peptide Repertoire: Proteases And Rementioning

confidence: 99%

The Other Function: Class II-Restricted Antigen Presentation by B Cells

et al. 2017

Self Cite

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Mature B lymphocytes (B cells) recognize antigens using their B cell receptor (BCR) and are activated to become antibody-producing cells. In addition, and integral to the development of a high-affinity antibodies, B cells utilize the specialized major histocompatibility complex class II (MHCII) antigen presentation pathway to process BCR-bound and internalized protein antigens and present selected peptides in complex with MHCII to CD4+ T cells. This interaction influences the fate of both types of lymphocytes and shapes immune outcomes. Specific, effective, and optimally timed antigen presentation by B cells requires well-controlled intracellular machinery, often regulated by the combined effects of several molecular events. Here, we delineate and summarize these events in four steps along the antigen presentation pathway: (1) antigen capture and uptake by B cells; (2) intersection of internalized antigen/BCRs complexes with MHCII in peptide-loading compartments; (3) generation and regulation of MHCII/peptide complexes; and (4) exocytic transport for presentation of MHCII/peptide complexes at the surface of B cells. Finally, we discuss modulation of the MHCII presentation pathway across B cell development and maturation to effector cells, with an emphasis on the shaping of the MHCII/peptide repertoire by two key antigen presentation regulators in B cells: HLA-DM and HLA-DO.

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pH-susceptibility of HLA-DO tunes DO/DM ratios to regulate HLA-DM catalytic activity

Cited by 26 publications

References 45 publications

B cells rapidly target antigen and surface-derived MHCII into peripheral degradative compartments

B cells rapidly target antigen and surface-derived MHCII into peripheral degradative compartments

HLA-DO Modulates the Diversity of the MHC-II Self-peptidome

The Other Function: Class II-Restricted Antigen Presentation by B Cells

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