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Revisiting the Coreceptor Function of Complement Receptor Type 2 (CR2, CD21); Coengagement With the B-Cell Receptor Inhibits the Activation, Proliferation, and Antibody Production of Human B Cells.

ABSTRACT: The positive coreceptor function of complement receptor type 2 [CR2 (CD21)] on B cells is generally accepted, although its role in the enhancement of antibody production had only been proven in mice. The importance of this phenomenon prompted reinvestigation of the functional consequences of coclustering CD21 and the B cell receptor (BCR) on primary human cells. We found that, at non-stimulatory concentrations of anti-IgG/A/M, coclustering the BCR and CR2 enhanced the Ca²⁺ response, while activation marker expression, cytokine production, proliferation, and antibody production were all inhibited upon the coengagement of CR2 and BCR on human B cells. Thus, the "textbook dogma" claiming that C3d acts as an adjuvant to enhance humoral immunity is relevant only to mice and not to humans.

SUBMITTER: Kovacs KG

PROVIDER: S-EPMC8047317 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Revisiting the Coreceptor Function of Complement Receptor Type 2 (CR2, CD21); Coengagement With the B-Cell Receptor Inhibits the Activation, Proliferation, and Antibody Production of Human B Cells.

Kovács Kristóf G KG Mácsik-Valent Bernadett B Matkó János J Bajtay Zsuzsa Z Erdei Anna A

Frontiers in immunology 20210401

The positive coreceptor function of complement receptor type 2 [CR2 (CD21)] on B cells is generally accepted, although its role in the enhancement of antibody production had only been proven in mice. The importance of this phenomenon prompted reinvestigation of the functional consequences of coclustering CD21 and the B cell receptor (BCR) on primary human cells. We found that, at non-stimulatory concentrations of anti-IgG/A/M, coclustering the BCR and CR2 enhanced the Ca<sup>2+</sup> response, w ...[more]

PMID: 33868238

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Project description:Complement receptors 1 and 2 (CR1/2 or CD35/CD21) recognize complement-opsonized antigens to initiate innate and adaptive immunity, respectively. CD35 stimulates phagocytosis on macrophages and antigen presentation on follicular dendritic cells (FDCs). CD21 helps activate B cells as part of the B cell coreceptor with CD19 and CD81. Differential splicing of transcripts from the mouse Cr2 gene generates isoforms with both shared and unique complement binding capacities and cell-type expression. In mouse models, genetic depletion of Cr2 causes either a delay or complete prevention of prion disease, but the relative importance of CD35 versus CD21 in promoting prion disease remains unknown. Here we show that both isoforms act as high-affinity cell surface prion receptors. However, mice lacking CD21 succumbed to terminal prion disease significantly later than mice lacking CD35 or wild-type and hemizygous mice. CD21-deficient mice contained fewer splenic prions than CD35 knockout mice early after infection that contributed to delayed prion neuroinvasion and terminal disease, despite forming follicular networks closer to proximal nerves. While we observed no difference in B cell networks, PrPC expression, or number of follicles, CD21-deficient mice formed more fragmented, less organized follicular networks with fewer Mfge8-positive FDCs and/or tingible body macrophages (TBMφs) than wild-type or CD35-deficient mice. In toto, these data demonstrate a more prominent role for CD21 for proper follicular development and organization leading to more efficient lymphoid prion replication and expedited prion disease than in mice expressing the CD35 isoform. IMPORTANCE Mammalian prion diseases are caused by prions, unique infectious agents composed primarily, if not solely, of a pathologic, misfolded form of a normal host protein, the cellular prion protein (PrPC). Prions replicate without a genetic blueprint, but rather contact PrPC and coerce it to misfold into more prions, which cause neurodegeneration akin to other protein-misfolding diseases like Alzheimer's disease. A single gene produces two alternatively spliced mRNA transcripts that encode mouse complement receptors CD21/35, which promote efficient prion replication in the lymphoid system and eventual movement to the brain. Here we show that CD21/35 are high-affinity prion receptors, but mice expressing only CD21 die from prion disease sooner than CD35-expressing mice, which contain less prions early after infection and exhibit delayed terminal disease, likely due to their less organized splenic follicles. Thus, CD21 appears to be more important for defining splenic architecture that influences prion pathogenesis.

Dataset Information

Revisiting the Coreceptor Function of Complement Receptor Type 2 (CR2, CD21); Coengagement With the B-Cell Receptor Inhibits the Activation, Proliferation, and Antibody Production of Human B Cells.

Publications

Revisiting the Coreceptor Function of Complement Receptor Type 2 (CR2, CD21); Coengagement With the B-Cell Receptor Inhibits the Activation, Proliferation, and Antibody Production of Human B Cells.

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