Analysis of H2-O Influence on Antigen Presentation by B Cells

Alfonso, Christopher; Williams, G. Stuart; Han, J O; Westberg, Johan A.; Winqvist, Ola; Karlsson, Lars

doi:10.4049/jimmunol.171.5.2331

Cited by 41 publications

(46 citation statements)

References 39 publications

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“…H2-O −/− B cells outcompeted WT B cells by ∼2-to 5-fold, but did not completely take over the GC niche. This suggests that H2-O-dependent modulation of Ag presentation may be subtle, which is supported by previous studies that examined presentation on the cellular level and found varying effects of H2-O depending on the specific epitope examined (9,(11)(12)(13)(14)(15)25). Nevertheless, small differences in Ag presentation, especially when considering a complex Ag mix containing many individual epitopes, could have a considerable impact on the immune response.…”

Section: Discussionsupporting

confidence: 55%

“…Studies using MHCII-peptide-specific Abs, TCR Tg T cells, or T-cell hybridomas have shown that H2-O variably and unpredictably affects the presentation of individual peptides (9,14,15). Therefore, rather than further study T-cell responses to the presentation of individual peptides, we measured the ability of GC B cells to obtain T-cell help from the pool of endogenous polyclonal CD4 + T cells.…”

Section: Np-specific H2-o −/− B Cells Preferentially Populate the Gc mentioning

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: 55%

Section: Np-specific H2-o −/− B Cells Preferentially Populate the Gc mentioning

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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“…2a, right panel). As previous studies have reported a requirement for the MHC-like molecule H-2DM in BCR-mediated antigen presentation, 46 we also performed antigen presentation assays using the A20 mutant 3A5, which lacks functional H-2DM. synthetic p84-104 peptide by A20-3A5 B cells was similar to that of A20 cells (Fig.…”

Section: Generation Of Aggrecan-specific B Cellsmentioning

confidence: 99%

Presentation of the candidate rheumatoid arthritis autoantigen aggrecan by antigen‐specific B cells induces enhanced CD4⁺ T helper type 1 subset differentiation

Hine

Pradipta

et al. 2012

Immunology

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Summary Effective immune responses require antigen uptake by antigen‐presenting cells (APC), followed by controlled endocytic proteolysis resulting in the generation of antigen‐derived peptide fragments that associate with intracellular MHC class II molecules. The resultant peptide–MHC class II complexes then move to the APC surface where they activate CD4+ T cells. Dendritic cells (DC), macrophages and B cells act as efficient APC. In many settings, including the T helper type 1 (Th1) ‐dependent, proteoglycan‐induced arthritis model of rheumatoid arthritis, accumulating evidence demonstrates that antigen presentation by B cells is required for optimal CD4+ T cell activation. The reasons behind this however, remain unclear. In this study we have compared the activation of CD4+ T cells specific for the proteoglycan aggrecan following antigen presentation by DC, macrophages and B cells. We show that aggrecan‐specific B cells are equally efficient APC as DC and macrophages and use similar intracellular antigen‐processing pathways. Importantly, we also show that antigen presentation by aggrecan‐specific B cells to TCR transgenic CD4+ T cells results in enhanced CD4+ T cell interferon‐γ production and Th1 effector sub‐set differentiation compared with that seen with DC. We conclude that preferential CD4+ Th1 differentiation may define the requirement for B cell APC function in both proteoglycan‐induced arthritis and rheumatoid arthritis.

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“…Hence, upon productive Ag presentation with the hybridoma's cognate I-A b -restricted Ag, the hybridoma would express eGFP. BMMfs from WT and Cybb 2/2 mice were exposed to 1 mg/ml HEL for 6 h and individual hybridomas were added and incubated with the BMMfs for 16 h. Presentation efficiency of each HEL epitope was determined by measuring eGFP expression by flow cytometry and is presented relative to GFP expression induced by nonspecific hybridoma activation by 50 ng/ml PMA and 1 mg/ml ionomycin (25,26).…”

Section: Assessment Of Pattern Of Intraphagosomal Proteolysismentioning

confidence: 99%

“…In vitro assessment of Ag processing and presentation (25,26) were stably transfected with a pcDNA3 construct that contained enhanced GFP (eGFP) under the control of a NFATenhanced IL-2 promoter (pNFATeGFP) as previously described (25)(26)(27)(28). Hence, upon productive Ag presentation with the hybridoma's cognate I-A b -restricted Ag, the hybridoma would express eGFP.…”

Section: Assessment Of Pattern Of Intraphagosomal Proteolysismentioning

confidence: 99%

NADPH Oxidase Modifies Patterns of MHC Class II–Restricted Epitopic Repertoires through Redox Control of Antigen Processing

Allan

Tailor

Balce

et al. 2014

The Journal of Immunology

106

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The chemistries within phagosomes of APCs mediate microbial destruction as well as generate peptides for presentation on MHC class II. The antimicrobial effector NADPH oxidase (NOX2), which generates superoxide within maturing phagosomes, has also been shown to regulate activities of cysteine cathepsins through modulation of the lumenal redox potential. Using real-time analyses of lumenal microenvironmental parameters, in conjunction with hydrolysis pattern assessment of phagocytosed proteins, we demonstrated that NOX2 activity not only affects levels of phagosomal proteolysis as previously shown, but also the pattern of proteolytic digestion. Additionally, it was found that NOX2 deficiency adversely affected the ability of bone marrow–derived macrophages, but not dendritic cells, to process and present the I-Ab–immunodominant peptide of the autoantigen myelin oligodendrocyte glycoprotein (MOG). Computational and experimental analyses indicated that the I-Ab binding region of the immunodominant peptide of MOG is susceptible to cleavage by the NOX2-controlled cysteine cathepsins L and S in a redox-dependent manner. Consistent with these findings, I-Ab mice that were deficient in the p47phox or gp91phox subunits of NOX2 were partially protected from MOG-induced experimental autoimmune encephalomyelitis and displayed compromised reactivation of MOG-specific CD4+ T cells in the CNS, despite eliciting a normal primary CD4+ T cell response to the inoculated MOG Ag. Taken together, this study demonstrates that the redox microenvironment within the phagosomes of APCs is a determinant in MHC class II repertoire production in a cell-specific and Ag-specific manner, which can ultimately impact susceptibility to CD4+ T cell–driven autoimmune disease processes.

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Analysis of H2-O Influence on Antigen Presentation by B Cells

Cited by 41 publications

References 39 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

Presentation of the candidate rheumatoid arthritis autoantigen aggrecan by antigen‐specific B cells induces enhanced CD4⁺ T helper type 1 subset differentiation

NADPH Oxidase Modifies Patterns of MHC Class II–Restricted Epitopic Repertoires through Redox Control of Antigen Processing

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Analysis of H2-O Influence on Antigen Presentation by B Cells

Cited by 41 publications

References 39 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

Presentation of the candidate rheumatoid arthritis autoantigen aggrecan by antigen‐specific B cells induces enhanced CD4+ T helper type 1 subset differentiation

NADPH Oxidase Modifies Patterns of MHC Class II–Restricted Epitopic Repertoires through Redox Control of Antigen Processing

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Presentation of the candidate rheumatoid arthritis autoantigen aggrecan by antigen‐specific B cells induces enhanced CD4⁺ T helper type 1 subset differentiation