Regulated Expression of Human Histocompatibility Leukocyte Antigen (HLA)-DO During Antigen-dependent and Antigen-independent Phases of B Cell Development

Chen, Xinjian; Laur, Oskar; Kambayashi, Taku; Sy, Li; Bray, Robert A.; Weber, Dominique A.; Karlsson, Lars; Jensen, Peter E.

doi:10.1084/jem.20012066

Cited by 74 publications

(136 citation statements)

References 46 publications

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“…These data show that, upon Ag encounter, H2-O −/− B cells have an advantage in entering the GC; however, once they have entered, H2-O −/− and WT B cells have a similar ability to contribute to the expanding GC B-cell pool. This is consistent with data showing that H2-O is down-regulated in WT GC B cells, making them functionally more similar to H2-O −/− B cells (22)(23)(24).…”

Section: Discussionsupporting

confidence: 92%

“…This suggests an important immunological function for H2-O in which H2-O establishes a higher threshold of Ag presentation for cells to commence the GC reaction. Down-regulation of H2-O upon GC entry allows Ag presentation to proceed more efficiently after the entry checkpoint has been passed (22)(23)(24). The GC reaction, albeit a vital part of the immune response, is also inherently dangerous because it combines the active mutagenic mechanisms of somatic hypermutation with rapid cellular proliferation (27).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

H2-O, a MHC class II-like protein, sets a threshold for B-cell entry into germinal centers

Draghi¹,

Denzin

2010

Proc. Natl. Acad. Sci. U.S.A.

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Upon antigen (Ag) encounter, B cells require T-cell help to enter the germinal center (GC). They obtain this help by presenting Agderived peptides on MHC class II (MHCII) for recognition by the T-cell receptor (TCR) of CD4 + T cells. Peptides are loaded onto MHCII in endosomal compartments in a process catalyzed by the MHCII-like protein H2-M (HLA-DM in humans). This process is modulated by another MHCII-like protein, H2-O (HLA-DO in humans). H2-O is a biochemical inhibitor of peptide loading onto MHCII; however, on the cellular level, it has been shown to have varying effects on Ag presentation. Thus, the function of H2-O in the adaptive immune response remains unclear. Here, we examine the effect of H2-O expression on the ability of Ag-specific B cells to enter the GC. We show that when Ag specific WT and H2-O −/− B cells are placed in direct competition, H2-O −/− B cells preferentially populate the GC. This advantage is confined to Ag-specific B cells and is due to their superior ability to obtain Ag-specific T-cell help when T-cell help is limiting. Overall, our work shows that H2-O expression reduces the ability of B cells to gain T-cell help and participate in the GC reaction.antigen processing | antigen presentation | H2-M | follicular helper T cells | HLA-DOA ntigen (Ag) processing and presentation on MHCII is central to T cell-dependent Ab-mediated immunity. During an immune response, Ag-specific naïve B cells recognize and internalize Ag via the B-cell receptor (BCR). The Ag is subsequently transported to late endosomes and lysosomes, where it is degraded into peptides, some of which are loaded onto MHC class II (MHCII) (1). These MHCII-peptide complexes are then displayed on the cell surface for recognition by cognate CD4 + T cells. This recognition event allows B cells to obtain T-cell help from a rare population of T cells known as CD4 + follicular helper T cells (T FH ). The interaction between the Ag-specific B cells and T FH cells is essential for B-cell entry into the germinal center (GC) (2).Peptide loading of MHCII is catalyzed by the nonclassical MHCII-like protein H2-M (HLA-DM in humans) (3-5). H2-M, which localizes to endosomes (6), promotes the removal of class IIassociated invariant chain peptides (CLIP) from the peptidebinding groove of MHCII. H2-M also stabilizes empty MHCII molecules and edits the final MHCII-bound peptide repertoire that is displayed at the cell surface to ensure that only long-lived MHCII-peptide complexes are presented (7). Another nonclassical MHCII-like protein, H2-O (HLA-DO in humans), also localizes to endosomes in B cells (8). H2-O forms a complex with H2-M and has been shown to inhibit or modulate the ability of H2-M to catalyze and edit MHCII peptide exchange (9-12). Surprisingly, H2-O-deficient mice exhibit only minor abnormalities in Ag presentation (11, 13).Ag presentation is important for many aspects of immunity, including initiating the GC response. Admission of B cells into the GC is a competitive process that is dependent upon help from Agspecific T F...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

H2-O, a MHC class II-like protein, sets a threshold for B-cell entry into germinal centers

Draghi¹,

Denzin

2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Results showed that both TgMed and TgHi bmDCs had substantial pools of free H-2M (ϳ90% and ϳ40%, respectively). In human primary B cells and B cell lines, ϳ50 -70% of cellular DM is complexed with DO (5,15,37). Thus, the fraction of H-2M molecules that are DO-associated in DO Tg DCs is similar to that in human B cells.…”

Section: Do Expressing Bmdcs Have Two Pools Of H-2mmentioning

confidence: 89%

“…However, recent studies have suggested that the function of DO may be more multifaceted (9,10). Depending on both the experimental system and the Ag studied, it has been shown that DO can inhibit (7,(11)(12)(13)(14)(15), promote (9,10,16), or have no effect (9,10,12) on class II-peptide loading. Collectively, these studies suggest that DO modifies the loading of specific peptides on to class II molecules, which results in a change in the class II-peptide repertoire (13).…”

mentioning

confidence: 99%

Ectopic Expression of HLA-DO in Mouse Dendritic Cells Diminishes MHC Class II Antigen Presentation

Fallas¹,

Tobin

Lou

et al. 2004

The Journal of Immunology

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The MHC class II-like molecule HLA-DM (DM) (H-2M in mice) catalyzes the exchange of CLIP for antigenic peptides in the endosomes of APCs. HLA-DO (DO) (H-2O in mice) is another class II-like molecule that is expressed in B cells, but not in other APCs. Studies have shown that DO impairs or modifies the peptide exchange activity of DM. To further evaluate the role of DO in Ag processing and presentation, we generated transgenic mice that expressed the human HLA-DOA and HLA-DOB genes under the control of a dendritic cell (DC)-specific promoter. Our analyses of DCs from these mice showed that as DO levels increased, cell surface levels of Ab-CLIP also increased while class II-peptide levels decreased. The presentation of some, but not all, exogenous Ags to T cells or T hybridomas was significantly inhibited by DO. Surprisingly, H-2M accumulated in DO-expressing DCs and B cells, suggesting that H-2O/DO prolongs the half-life of H-2M. Overall, our studies showed that DO expression impaired H-2M function, resulting in Ag-specific down-modulation of class II Ag processing and presentation.

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“…in monocytes (4,12). The decrease in relative CLIP/class II levels seen following GM-CSF treatment may reflect a change in DM, Ii, and/or DO expression, and this was tested directly.…”

Section: Gm-csf Increases Total Protein Levels Of Dr Dm II and Do␣mentioning

confidence: 99%

Regulation of the Class II MHC Pathway in Primary Human Monocytes by Granulocyte-Macrophage Colony-Stimulating Factor

Hornell

Beresford

Bushey

et al. 2003

The Journal of Immunology

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GM-CSF stimulates the growth and differentiation of hematopoietic progenitors and also affects mature cell function. These effects have led to the use of GM-CSF as a vaccine adjuvant with promising results; however, the mechanisms underlying GM-CSF-mediated immune potentiation are incompletely understood. In this study, we investigated the hypothesis that the immune stimulatory role of GM-CSF is in part due to effects on class II MHC Ag presentation. We find that, in primary human monocytes treated for 24–48 h, GM-CSF increases surface class II MHC expression and decreases the relative level of the invariant chain-derived peptide, CLIP, bound to surface class II molecules. GM-CSF also increases expression of the costimulatory molecules CD86 and CD40, but not the differentiation marker CD1a or CD16. Furthermore, GM-CSF-treated monocytes are better stimulators in a mixed leukocyte reaction. Additional analyses of the class II pathway revealed that GM-CSF increases total protein and RNA levels of HLA-DR, DM, and DOα. Expression of class II transactivator (CIITA) types I and III, but not IV, transcripts increases in response to GM-CSF. Furthermore, GM-CSF increases the amount of CIITA associated with the DR promoter. Thus, our data argue that the proinflammatory role of GM-CSF is mediated in part through increased expression of key molecules involved in the class II MHC pathway via induction of CIITA.

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Regulated Expression of Human Histocompatibility Leukocyte Antigen (HLA)-DO During Antigen-dependent and Antigen-independent Phases of B Cell Development

Cited by 74 publications

References 46 publications

H2-O, a MHC class II-like protein, sets a threshold for B-cell entry into germinal centers

H2-O, a MHC class II-like protein, sets a threshold for B-cell entry into germinal centers

Ectopic Expression of HLA-DO in Mouse Dendritic Cells Diminishes MHC Class II Antigen Presentation

Regulation of the Class II MHC Pathway in Primary Human Monocytes by Granulocyte-Macrophage Colony-Stimulating Factor

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