Ubiquitination by March-I prevents MHC class II recycling and promotes MHC class II turnover in antigen-presenting cells

MHC class II (MHC-II)-dependent antigen presentation by antigen-presenting cells (APCs) is carefully controlled to achieve specificity of immune responses; the regulated assembly and degradation of antigenic peptide–MHC-II complexes (pMHC-II) is one aspect of such control. In this study, we have examined the role of ubiquitination in regulating pMHC-II biosynthesis, endocytosis, recycling, and turnover in APCs. By using APCs obtained from MHC-II ubiquitination mutant mice, we find that whereas ubiquitination does not affect pMHC-II formation in dendritic cells (DCs), it does promote the subsequent degradation of newly synthesized pMHC-II. Acute activation of DCs or B cells terminates expression of the MHC-II E3 ubiquitin ligase March-I and prevents pMHC-II ubiquitination. Most importantly, this change results in very efficient pMHC-II recycling from the surface of DCs and B cells, thereby preventing targeting of internalized pMHC-II to lysosomes for degradation. Biochemical and functional assays confirmed that pMHC-II turnover is suppressed in MHC-II ubiquitin mutant DCs or by acute activation of wild-type DCs. These studies demonstrate that acute APC activation blocks the ubiquitin-dependent turnover of pMHC-II by promoting efficient pMHC-II recycling and preventing lysosomal targeting of internalized pMHC-II, thereby enhancing pMHC-II stability for efficient antigen presentation to CD4 T cells.

Download Full-text

Class II MHC/Peptide Complexes on T Cell Antigen-Presenting Cells: Agonistic Antigen Recognition Inhibits Subsequent Antigen Presentation

Cellular Immunology ◽

10.1006/cimm.1998.1301 ◽

1998 ◽

Vol 186 (2) ◽

pp. 111-120 ◽

Cited By ~ 13

Author(s):

Mark D. Mannie ◽

John P. Nardella ◽

Gregory A. White ◽

Paula Y. Arnold ◽

Daniel K. Davidian

Keyword(s):

T Cell ◽

Antigen Presentation ◽

Antigen Presenting Cells ◽

Class Ii ◽

Antigen Recognition ◽

Cell Antigen ◽

Class Ii Mhc ◽

Peptide Complexes ◽

Antigen Presenting

Download Full-text

Role of antigen-presenting cells in the polarized development of helper T cell subsets: evidence for differential cytokine production by Th0 cells in response to antigen presentation by B cells and macrophages

European Journal of Immunology ◽

10.1002/eji.1830241037 ◽

1994 ◽

Vol 24 (10) ◽

pp. 2506-2514 ◽

Cited By ~ 53

Author(s):

David D. Duncan ◽

Susan L. Swain

Keyword(s):

T Cell ◽

B Cells ◽

Antigen Presentation ◽

Cytokine Production ◽

Antigen Presenting Cells ◽

T Cell Subsets ◽

Helper T Cell ◽

Antigen Presenting

Download Full-text

Trogocytosis of peptide–MHC class II complexes from dendritic cells confers antigen-presenting ability on basophils

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1615973114 ◽

2017 ◽

Vol 114 (5) ◽

pp. 1111-1116 ◽

Cited By ~ 50

Author(s):

Kensuke Miyake ◽

Nozomu Shiozawa ◽

Toshihisa Nagao ◽

Soichiro Yoshikawa ◽

Yoshinori Yamanishi ◽

...

Keyword(s):

Dendritic Cells ◽

Cell Differentiation ◽

Cell Surface ◽

Mhc Class Ii ◽

Antigen Presenting Cells ◽

Class Ii ◽

Gm Csf ◽

Mhc Ii ◽

Th2 Cell ◽

Antigen Presenting

Th2 immunity plays important roles in both protective and allergic responses. Nevertheless, the nature of antigen-presenting cells responsible for Th2 cell differentiation remains ill-defined compared with the nature of the cells responsible for Th1 and Th17 cell differentiation. Basophils have attracted attention as a producer of Th2-inducing cytokine IL-4, whereas their MHC class II (MHC-II) expression and function as antigen-presenting cells are matters of considerable controversy. Here we revisited the MHC-II expression on basophils and explored its functional relevance in Th2 cell differentiation. Basophils generated in vitro from bone marrow cells in culture with IL-3 plus GM-CSF displayed MHC-II on the cell surface, whereas those generated in culture with IL-3 alone did not. Of note, these MHC-II–expressing basophils showed little or no transcription of the corresponding MHC-II gene. The GM-CSF addition to culture expanded dendritic cells (DCs) other than basophils. Coculture of basophils and DCs revealed that basophils acquired peptide–MHC-II complexes from DCs via cell contact-dependent trogocytosis. The acquired complexes, together with CD86, enabled basophils to stimulate peptide-specific T cells, leading to their proliferation and IL-4 production, indicating that basophils can function as antigen-presenting cells for Th2 cell differentiation. Transfer of MHC-II from DCs to basophils was also detected in draining lymph nodes of mice with atopic dermatitis-like skin inflammation. Thus, the present study defined the mechanism by which basophils display MHC-II on the cell surface and appears to reconcile some discrepancies observed in previous studies.

Download Full-text

Glatiramer acetate immune modulates B-cell antigen presentation in treatment of MS

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000698 ◽

2020 ◽

Vol 7 (3) ◽

pp. e698 ◽

Cited By ~ 3

Author(s):

Darius Häusler ◽

Zivar Hajiyeva ◽

Jan W. Traub ◽

Scott S. Zamvil ◽

Patrice H. Lalive ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Antigen Presentation ◽

Glatiramer Acetate ◽

Mhc Class Ii ◽

Class Ii ◽

Cell Antigen ◽

Antigen Presenting

ObjectiveWe examined the effect of glatiramer acetate (GA) on B-cell maturation, differentiation, and antigen presentation in MS and experimental autoimmune encephalomyelitis (EAE).MethodsA cross-sectional study of blood samples from 20 GA-treated and 18 untreated patients with MS was performed by flow cytometry; 6 GA-treated patients with MS were analyzed longitudinally. GA-mediated effects on B-cell antigen-presenting function were investigated in EAE, or, alternatively, B cells were treated with GA in vitro using vehicle as a control.ResultsIn MS, GA diminished transitional B-cell and plasmablast frequency, downregulated CD69, CD25, and CD95 expression, and decreased TNF-α production, whereas IL-10 secretion and MHC Class II expression were increased. In EAE, we observed an equivalent dampening of proinflammatory B-cell properties and an enhanced expression of MHC Class II. When used as antigen-presenting cells for activation of naive T cells, GA-treated B cells promoted development of regulatory T cells, whereas proinflammatory T-cell differentiation was diminished.ConclusionsGA immune modulates B-cell function in EAE and MS and efficiently interferes with pathogenic B cell–T cell interaction.

Download Full-text

Role of Newly Synthesized MHC Class II Molecules in Antigen-Specific Antigen Presentation by B cells

Immunobiology ◽

10.1016/s0171-2985(11)80154-3 ◽

1995 ◽

Vol 193 (1) ◽

pp. 42-58 ◽

Cited By ~ 4

Author(s):

Takehiro Kokuho ◽

Hideo Nariuchi ◽

Yuichi Gyotoku ◽

Terutaka Kakiuchi

Keyword(s):

B Cells ◽

Antigen Presentation ◽

Mhc Class Ii ◽

Specific Antigen ◽

Class Ii ◽

Mhc Class Ii Molecules

Download Full-text

Ligation of MHC Class II Induces PKC-Dependent Clathrin-Mediated Endocytosis of MHC Class II

Cells ◽

10.3390/cells9081810 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1810

Author(s):

Kento Masaki ◽

Yuhji Hiraki ◽

Hiroka Onishi ◽

Yuka Satoh ◽

Paul A. Roche ◽

...

Keyword(s):

T Cells ◽

Mhc Class Ii ◽

Cd4 T Cells ◽

Surface Expression ◽

Class Ii ◽

Cellular Functions ◽

Mhc Ii ◽

Histocompatibility Complex ◽

Class Ii Mhc ◽

Antigen Presenting

In addition to antigen presentation to CD4+ T cells, aggregation of cell surface major histocompatibility complex class II (MHC-II) molecules induces signal transduction in antigen presenting cells that regulate cellular functions. We previously reported that crosslinking of MHC-II induced the endocytosis of MHC-II, which was associated with decreased surface expression levels in murine dendritic cells (DCs) and resulted in impaired activation of CD4+ T cells. However, the downstream signal that induces MHC-II endocytosis remains to be elucidated. In this study, we found that the crosslinking of MHC-II induced intracellular Ca2+ mobilization, which was necessary for crosslinking-induced MHC-II endocytosis. We also found that these events were suppressed by inhibitors of Syk and phospholipase C (PLC). Treatments with a phorbol ester promoted MHC-II endocytosis, whereas inhibitors of protein kinase C (PKC) suppressed crosslinking-induced endocytosis of MHC-II. These results suggest that PKC could be involved in this process. Furthermore, crosslinking-induced MHC-II endocytosis was suppressed by inhibitors of clathrin-dependent endocytosis. Our results indicate that the crosslinking of MHC-II could stimulate Ca2+ mobilization and induce the clathrin-dependent endocytosis of MHC-II in murine DCs.

Download Full-text

CD83 influences cell-surface MHC class II expression on B cells and other antigen-presenting cells

International Immunology ◽

10.1093/intimm/dxm067 ◽

2007 ◽

Vol 19 (8) ◽

pp. 977-992 ◽

Cited By ~ 32

Author(s):

Y. Kuwano ◽

C. M. Prazma ◽

N. Yazawa ◽

R. Watanabe ◽

N. Ishiura ◽

...

Keyword(s):

B Cells ◽

Cell Surface ◽

Mhc Class Ii ◽

Antigen Presenting Cells ◽

Class Ii ◽

Antigen Presenting

Download Full-text

Tuning DO:DM ratios modulates MHC class II immunopeptidomes

10.1101/2021.10.05.463141 ◽

2021 ◽

Author(s):

Niclas E Olsson ◽

Wei Jiang ◽

Lital N Adler ◽

Elizabeth Mellins ◽

Joshua E Elias

Keyword(s):

Antigen Presentation ◽

Mhc Class Ii ◽

Computational Prediction ◽

Class Ii ◽

The Body ◽

Research Strategies ◽

Mhc Ii ◽

Wide Range ◽

Health And Disease ◽

Antigen Presenting

Major histocompatibility complex class II (MHC-II) antigen presentation underlies a wide range of immune responses in health and disease. However, how MHC-II antigen presentation is regulated by the peptide-loading catalyst HLA-DM (DM), its associated modulator, HLA-DO (DO), is incompletely understood. This is due largely to technical limitations: model antigen presenting cell (APC) systems that express these MHC-II peptidome regulators at physiologically variable levels have not been described. Likewise, computational prediction tools that account for DO and DM activities are not presently available. To address these gaps, we created a panel of single MHC-II allele, HLA-DR4-expressing APC lines that cover a wide range of DO:DM ratio states. Using a combined immunopeptidomic and proteomic discovery strategy, we measured the effects DO:DM ratios have on peptide presentation by surveying over 10,000 unique DR4-presented peptides. The resulting data provide insight into peptide characteristics that influence their presentation with increasing DO:DM ratios. These include DM-sensitivity, peptide abundance, binding affinity and motif, peptide length and register positioning on the source protein. These findings have implications for designing improved HLA-II prediction algorithms and research strategies for dissecting the variety of functions that different APCs serve in the body.

Download Full-text

Targeting Antigen-Presenting Cells in Multiple Sclerosis Treatment

Applied Sciences ◽

10.3390/app11188557 ◽

2021 ◽

Vol 11 (18) ◽

pp. 8557

Author(s):

Piotr Szpakowski ◽

Dominika Ksiazek-Winiarek ◽

Andrzej Glabinski

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Dendritic Cells ◽

Antigen Presentation ◽

Mhc Class Ii ◽

Antigen Presenting Cells ◽

Class Ii ◽

The Central Nervous System ◽

Antigen Presenting ◽

Myelin Antigens

Multiple sclerosis (MS) is common neurological disease of the central nervous system (CNS) affecting mostly young adults. Despite decades of studies, its etiology and pathogenesis are not fully unraveled and treatment is still insufficient. The vast majority of studies suggest that the immune system plays a major role in MS development. This is also supported by the effectiveness of currently available MS treatments that target immunocompetent cells. In this review, the role of antigen-presenting cells (APC) in MS development as well as the novel therapeutic options targeting those cells in MS are presented. It is known that in MS, peripheral self-antigen-specific immune cells are activated during antigen presentation process and they enter the CNS through the disrupted blood–brain barrier (BBB). Myelin-reactive CD4+ T-cells can be activated by dendritic cells, infiltrating macrophages, microglia cells, or B-cells, which all express MHC class II molecules. There are also suggestions that brain endothelial cells may act as non-professional APCs and present myelin-specific antigens with MHC class II. Similarly, astrocytes, the major glial cells in the CNS, were shown to act as non-professional APCs presenting myelin antigens to autoreactive T-cells. Several currently available MS drugs such as natalizumab, fingolimod, alemtuzumab, and ocrelizumab may modulate antigen presentation in MS. Another way to use this mechanism in MS treatment may be the usage of specific tolerogenic dendritic cells or the induction of tolerance to myelin antigens by peptide vaccines.

Download Full-text