scholarly journals Ubiquitin-mediated fluctuations in MHC class II facilitate efficient germinal center B cell responses

2016 ◽  
Vol 213 (6) ◽  
pp. 993-1009 ◽  
Author(s):  
Oliver Bannard ◽  
Simon J. McGowan ◽  
Jonatan Ersching ◽  
Satoshi Ishido ◽  
Gabriel D. Victora ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Mhc Class Ii ◽  
Somatic Hypermutation ◽  
Ectopic Expression ◽  
Cell Receptor ◽  
Class Ii ◽  
Affinity Maturation ◽  
Efficiency Of Selection ◽  
T Cell Help

Antibody affinity maturation occurs in germinal centers (GCs) through iterative rounds of somatic hypermutation and selection. Selection involves B cells competing for T cell help based on the amount of antigen they capture and present on their MHC class II (MHCII) proteins. How GC B cells are able to rapidly and repeatedly transition between mutating their B cell receptor genes and then being selected shortly after is not known. We report that MHCII surface levels and degradation are dynamically regulated in GC B cells. Through ectopic expression of a photoconvertible MHCII-mKikGR chimeric gene, we found that individual GC B cells differed in the rates of MHCII protein turnover. Fluctuations in surface MHCII levels were dependent on ubiquitination and the E3 ligase March1. Increases in March1 expression in centroblasts correlated with decreases in surface MHCII levels, whereas CD83 expression in centrocytes helped to stabilize MHCII at that stage. Defects in MHCII ubiquitination caused GC B cells to accumulate greater amounts of a specific peptide–MHCII (pMHCII), suggesting that MHCII turnover facilitates the replacement of old complexes. We propose that pMHCII complexes are periodically targeted for degradation in centroblasts to favor the presentation of recently acquired antigens, thereby promoting the fidelity and efficiency of selection.

scholarly journals CD40 ligand and MHC class II expression are essential for human peripheral B cell tolerance

2007 ◽  
Vol 204 (7) ◽  
pp. 1583-1593 ◽  
Author(s):  
Maxime Hervé ◽  
Isabelle Isnardi ◽  
Yen-shing Ng ◽  
James B. Bussel ◽  
Hans D. Ochs ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Mhc Class Ii ◽  
Somatic Hypermutation ◽  
Cd40 Ligand ◽  
Class Ii ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
The Impact

Hyper-IgM (HIGM) syndromes are primary immunodeficiencies characterized by defects of class switch recombination and somatic hypermutation. HIGM patients who carry mutations in the CD40-ligand (CD40L) gene expressed by CD4+ T cells suffer from recurrent infections and often develop autoimmune disorders. To investigate the impact of CD40L–CD40 interactions on human B cell tolerance, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from three CD40L-deficient patients. Antibody characteristics and reactivity from CD40L-deficient new emigrant B cells were similar to those from healthy donors, suggesting that CD40L–CD40 interactions do not regulate central B cell tolerance. In contrast, mature naive B cells from CD40L-deficient patients expressed a high proportion of autoreactive antibodies, including antinuclear antibodies. Thus, CD40L–CD40 interactions are essential for peripheral B cell tolerance. In addition, a patient with the bare lymphocyte syndrome who could not express MHC class II molecules failed to counterselect autoreactive mature naive B cells, suggesting that peripheral B cell tolerance also depends on major histocompatibility complex (MHC) class II–T cell receptor (TCR) interactions. The decreased frequency of MHC class II–restricted CD4+ regulatory T cells in CD40L-deficient patients suggests that these T cells may mediate peripheral B cell tolerance through CD40L–CD40 and MHC class II–TCR interactions.

scholarly journals Dynamics of Major Histocompatibility Complex Class II Compartments during B Cell Receptor–mediated Cell Activation

2002 ◽  
Vol 195 (4) ◽  
pp. 461-472 ◽  
Author(s):  
Danielle Lankar ◽  
Hélène Vincent-Schneider ◽  
Volker Briken ◽  
Takeaki Yokozeki ◽  
Graça Raposo ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Mhc Class Ii ◽  
Cell Receptor ◽  
Class Ii ◽  
B Cell Receptor ◽  
Cathepsin S ◽  
Invariant Chain ◽  
Histocompatibility Complex ◽  
Mhc Class Ii Molecules

Antigen recognition by clonotypic B cell receptor (BcR) is the first step of B lymphocytes differentiation into plasmocytes. This B cell function is dependent on efficient major histocompatibility complex (MHC) class II–restricted presentation of BcR-bound antigens. In this work, we analyzed the subcellular mechanisms underlying antigen presentation after BcR engagement on B cells. In quiescent B cells, we found that MHC class II molecules mostly accumulated at the cell surface and in an intracellular pool of tubulovesicular structures, whereas H2-M molecules were mostly detected in distinct lysosomal compartments devoid of MHC class II. BcR stimulation induced the transient intracellular accumulation of MHC class II molecules in newly formed multivesicular bodies (MVBs), to which H2-M was recruited. The reversible downregulation of cathepsin S activity led to the transient accumulation of invariant chain–MHC class II complexes in MVBs. A few hours after BcR engagement, cathepsin S activity increased, the p10 invariant chain disappeared, and MHC class II–peptide complexes arrived at the plasma membrane. Thus, BcR engagement induced the transient formation of antigen-processing compartments, enabling antigen-specific B cells to become effective antigen-presenting cells.

scholarly journals Induction of human IgE synthesis requires interleukin 4 and T/B cell interactions involving the T cell receptor/CD3 complex and MHC class II antigens.

1989 ◽  
Vol 169 (4) ◽  
pp. 1295-1307 ◽  
Author(s):  
D Vercelli ◽  
H H Jabara ◽  
K Arai ◽  
R S Geha
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Mhc Class Ii ◽  
Cell Receptor ◽  
Cell Interaction ◽  
Class Ii ◽  
Ige Synthesis ◽  
Mhc Class Ii Antigens ◽  
Class Ii Antigens

The induction of IgE synthesis by IL-4 requires T cells and monocytes, as well as T cell- and monocyte-derived cytokines. Optimal cytokine combinations, however, fail to induce highly purified B cells to secrete IgE, indicating that additional signals are required. We show herein that the induction of human IgE synthesis by rIL-4 requires cognate interaction between the T cell receptor/CD3 complex on T cells and MHC class II antigens on B cells: mAbs directed against these molecules completely blocked IL-4-dependent IgE induction. mAbs against cell adhesion molecules (CD2, CD4, LFA-1) also inhibited IgE synthesis induced by IL-4, confirming that cell-cell contact is necessary for IgE induction. The requirement for cognate T/B cell interaction was further shown by comparing the IgE-inducing ability of two human IL-4-producing alloreactive T cell clones: F6, which recognizes MHC class II antigens on both B cells and monocytes, and A1, which recognizes an HLA-DP-associated epitope expressed on monocytes, but not on B cells. When incubated with B cells and monocytes from a normal donor bearing the appropriate alloantigen, clone F6, but not clone A1, induced vigorous IgE synthesis, although both clones proliferated and secreted IL-4. Taken together, our results suggest that at least two, possibly synergizing, signals are required for the T cell-dependent induction of IgE synthesis by B cells: one signal is delivered by cognate T/B cell interaction, the other by T cell-derived IL-4.

scholarly journals Delivery of B Cell Receptor–internalized Antigen to Endosomes and Class II Vesicles

1997 ◽  
Vol 186 (8) ◽  
pp. 1299-1306 ◽  
Author(s):  
James R. Drake ◽  
Paul Webster ◽  
John C. Cambier ◽  
Ira Mellman
Keyword(s):  
B Cells ◽  
B Cell ◽  
Antigen Processing ◽  
Specific Antigen ◽  
Cell Receptor ◽  
Class Ii ◽  
Time Frame ◽  
B Cell Receptor ◽  
Subcellular Compartment ◽  
Endocytic Vesicles

B cell receptor (BCR)-mediated antigen processing is a mechanism that allows class II–restricted presentation of specific antigen by B cells at relatively low antigen concentrations. Although BCR-mediated antigen processing and class II peptide loading may occur within one or more endocytic compartments, the functions of these compartments and their relationships to endosomes and lysosomes remain uncertain. In murine B cells, at least one population of class II– containing endocytic vesicles (i.e., CIIV) has been identified and demonstrated to be distinct both physically and functionally from endosomes and lysosomes. We now demonstrate the delivery of BCR-internalized antigen to CIIV within the time frame during which BCR-mediated antigen processing and formation of peptide–class II complexes occurs. Only a fraction of the BCR-internalized antigen was delivered to CIIV, with the majority of internalized antigen being delivered to lysosomes that are largely class II negative. The extensive colocalization of BCR-internalized antigen and newly synthesized class II molecules in CIIV suggests that CIIV may represent a specialized subcellular compartment for BCR-mediated antigen processing. Additionally, we have identified a putative CIIV-marker protein, immunologically related to the Igα subunit of the BCR, which further illustrates the unique nature of these endocytic vesicles.

scholarly journals Germinal center reutilization by newly activated B cells

2009 ◽  
Vol 206 (13) ◽  
pp. 2907-2914 ◽  
Author(s):  
Tanja A. Schwickert ◽  
Boris Alabyev ◽  
Tim Manser ◽  
Michel C. Nussenzweig
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Somatic Hypermutation ◽  
Affinity Maturation ◽  
Anatomical Structures ◽  
Class Switch ◽  
Cell Clones ◽  
T Cell Help ◽  
Activated B Cells

Germinal centers (GCs) are specialized structures in which B lymphocytes undergo clonal expansion, class switch recombination, somatic hypermutation, and affinity maturation. Although these structures were previously thought to contain a limited number of isolated B cell clones, recent in vivo imaging studies revealed that they are in fact dynamic and appear to be open to their environment. We demonstrate that B cells can colonize heterologous GCs. Invasion of primary GCs after subsequent immunization is most efficient when T cell help is shared by the two immune responses; however, it also occurs when the immune responses are entirely unrelated. We conclude that GCs are dynamic anatomical structures that can be reutilized by newly activated B cells during immune responses.

scholarly journals Signatures of B Cell Receptor Repertoire Following Pneumocystis Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Han Sun ◽  
Hu-Qin Yang ◽  
Kan Zhai ◽  
Zhao-Hui Tong
Keyword(s):  
B Cells ◽  
B Cell ◽  
Single Cell ◽  
Plasma Cells ◽  
Somatic Hypermutation ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Receptor Repertoire ◽  
Elevated Expression ◽  
Pneumocystis Infection

B cells play vital roles in host defense against Pneumocystis infection. However, the features of the B cell receptor (BCR) repertoire in disease progression remain unclear. Here, we integrated single-cell RNA sequencing and single-cell BCR sequencing of immune cells from mouse lungs in an uninfected state and 1–4 weeks post-infection in order to illustrate the dynamic nature of B cell responses during Pneumocystis infection. We identified continuously increased plasma cells and an elevated ratio of (IgA + IgG) to (IgD + IgM) after infection. Moreover, Pneumocystis infection was associated with an increasing naïve B subset characterized by elevated expression of the transcription factor ATF3. The proportion of clonal expanded cells progressively increased, while BCR diversity decreased. Plasma cells exhibited higher levels of somatic hypermutation than naïve B cells. Biased usage of V(D)J genes was observed, and the usage frequency of IGHV9-3 rose. Overall, these results present a detailed atlas of B cell transcriptional changes and BCR repertoire features in the context of Pneumocystis infection, which provides valuable information for finding diagnostic biomarkers and developing potential immunotherapeutic targets.

scholarly journals Mechanisms behind Functional Avidity Maturation in T Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Marina Rode von Essen ◽  
Martin Kongsbak ◽  
Carsten Geisler
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Somatic Hypermutation ◽  
Cell Receptor ◽  
Affinity Maturation ◽  
Functional Avidity ◽  
Cell Clones ◽  
Genes Encoding ◽  
Avidity Maturation

During an immune response antigen-primed B-cells increase their antigen responsiveness by affinity maturation mediated by somatic hypermutation of the genes encoding the antigen-specific B-cell receptor (BCR) and by selection of higher-affinity B cell clones. Unlike the BCR, the T-cell receptor (TCR) cannot undergo affinity maturation. Nevertheless, antigen-primed T cells significantly increase their antigen responsiveness compared to antigen-inexperienced (naïve) T cells in a process called functional avidity maturation. This paper covers studies that describe differences in T-cell antigen responsiveness during T-cell differentiation along with examples of the mechanisms behind functional avidity maturation in T cells.

scholarly journals Both IFN-γ and IL-4 Induce MHC Class II Expression at the Surface of Mouse Pro-B Cells

1997 ◽  
Vol 5 (2) ◽  
pp. 115-120 ◽  
Author(s):  
Suzanne Lombard-Platet ◽  
Valerie Meyer ◽  
Rhodri Ceredig
Keyword(s):  
B Cells ◽  
B Cell ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Invariant Chain ◽  
B Cell Differentiation ◽  
Cell Clones ◽  
Ifn Γ ◽  
B Lymphoid ◽  
Mhc Class Ii Molecules

Pro-B cells are early B-cell progenitors that retain macrophage potential. We have studied MHC class II molecules and invariant chain inducibility on four class II negative mouse pro- B-cell clones. We analyzed the effects of IL-4 and IFN-γ, which represent the major inducers of class II in the B-lymphoid and monocytic/macrophage lineages, respectively. After 48 h of treatment with either cytokine, three pro-B-cell clones (C2.13, A1.5, and F2.2) expressed intracellular invariant chain and cell-surface class II molecules. One clone (D2.1) remained negative. As already reported, more differentiated 70Z/3 pre-B cells were inducible by IL-4 only. These data suggest that the induction of class II and invariant-chain genes are subject to regulation throughout B-cell differentiation.

scholarly journals Negligible Class II MHC Presentation of B Cell Receptor-Derived Peptides by High Density Resting B Cells

2002 ◽  
Vol 168 (8) ◽  
pp. 3865-3873 ◽  
Author(s):  
Christopher M. Snyder ◽  
Xianghua Zhang ◽  
Lawrence J. Wysocki
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
Class Ii ◽  
B Cell Receptor ◽  
High Density ◽  
Class Ii Mhc ◽  
Mhc Presentation
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