Expression Patterns of H2-O in Mouse B Cells and Dendritic Cells Correlate with Cell Function

Fallas, Jennifer L.; Yi, Whikun; Draghi, Nicole A.; O’Rourke, Helen M.; Denzin, Lisa K.

doi:10.4049/jimmunol.178.3.1488

Cited by 46 publications

(54 citation statements)

References 74 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: 81%

“…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: 81%

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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“…Coexpression of DO can also reduce DM function. DO is found in naive B cells, specific immature DC subsets, medullary thymic epithelial cells, and in cells lining Hassall's corpuscles, a thymic structure involved in selection of regulatory T cells (6,8,9,64,65). These cells are involved in thymic selection and maintenance of peripheral tolerance, suggesting that variation in CLIP affinity also may be influential in establishment and maintenance of tolerance.…”

Section: Discussionmentioning

confidence: 99%

Posttranslational Regulation ofI-Edby Affinity for CLIP

Rinderknecht

Belmares

Catanzarite

et al. 2007

The Journal of Immunology

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Several MHC class II alleles linked with autoimmune diseases form unusually low stability complexes with CLIP, leading us to hypothesize that this is an important feature contributing to autoimmune pathogenesis. To investigate cellular consequences of altering class II/CLIP affinity, we evaluated invariant chain (Ii) mutants with varying CLIP affinity for a mouse class II allele, I-Ed, which has low affinity for wild-type CLIP and is associated with a mouse model of spontaneous, autoimmune joint inflammation. Increasing CLIP affinity for I-Ed resulted in increased cell surface and total cellular abundance and half-life of I-Ed. This reveals a post-endoplasmic reticulum chaperoning capacity of Ii via its CLIP peptides. Quantitative effects on I-Ed were less pronounced in DM-expressing cells, suggesting complementary chaperoning effects mediated by Ii and DM, and implying that the impact of allelic variation in CLIP affinity on immune responses will be highest in cells with limited DM activity. Differences in the ability of cell lines expressing wild-type or high-CLIP-affinity mutant Ii to present Ag to T cells suggest a model in which increased CLIP affinity for class II serves to restrict peptide loading to DM-containing compartments, ensuring proper editing of antigenic peptides.

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“…36 Interestingly, the recent demonstrations of DO expression in specific DC subsets argue against a specific role in B cells in the context of the surface immunoglobulin antigen uptake. [37][38][39] Still, it is now accepted that H2-DO and DO 'modulate' MHC class II antigen processing. 32,34,36,40 In human B lymphocytes, as opposed to their mouse counterpart, the majority of DO molecules was found associated with DM 30,36,39,41 and this association allows DO to egress the ER.…”

Section: Introductionmentioning

confidence: 99%

“…[37][38][39] Still, it is now accepted that H2-DO and DO 'modulate' MHC class II antigen processing. 32,34,36,40 In human B lymphocytes, as opposed to their mouse counterpart, the majority of DO molecules was found associated with DM 30,36,39,41 and this association allows DO to egress the ER. 29,42 The lack of a recognizable di-basic ER retention motif (RXR or KKXX) suggests that the assembled DOab heterodimer is improperly folded in the absence of DM and most probably unstable.…”

Section: Introductionmentioning

confidence: 99%

Evidence for a human leucocyte antigen‐DM‐induced structural change in human leucocyte antigen‐DOβ

et al. 2009

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SummaryHuman leucocyte antigen (HLA)-DO is a non-classical major histocompatibility complex class II molecule which modulates the function of HLA-DM and the loading of antigenic peptides on molecules such as HLA-DR. The bulk of HLA-DO associates with HLA-DM and this interaction is critical for HLA-DO egress from the endoplasmic reticulum. HLA-DM assists the early steps of HLA-DO maturation presumably through the stabilization of the interactions between the N-terminal regions of the a and b chains. To evaluate a possible role for HLA-DM in influencing the conformation of HLA-DO, we made use of a monoclonal antibody, Mags.DO5, that was raised against HLA-DO/DM complexes. Using transfected cells expressing mismatched heterodimers between HLA-DR and -DO chains, we found that the epitope for Mags.DO5 is located on the DOb chain and that Mags.DO5 reactivity was increased upon cotransfection with HLA-DM. Our results suggest that HLA-DM influences the folding of HLA-DO in the endoplasmic reticulum. A mutant HLA-DO showing reduced capacity for endoplasmic reticulum egress was better recognized by Mags.DO5 in the presence of HLA-DM. On the other hand, an HLA-DO mutant capable of endoplasmic reticulum egress on its own was efficiently recognized by Mags.DO5, irrespective of the presence of HLA-DM. Taken together, our results suggest that HLA-DM acts as a private chaperone, directly assisting the folding of HLA-DO to promote egress from the endoplasmic reticulum.

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Expression Patterns of H2-O in Mouse B Cells and Dendritic Cells Correlate with Cell Function

Cited by 46 publications

References 74 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

Posttranslational Regulation ofI-Edby Affinity for CLIP

Evidence for a human leucocyte antigen‐DM‐induced structural change in human leucocyte antigen‐DOβ

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