New Insights into the Early Molecular Events Underlying B Cell Activation

Harwood, Naomi E.; Batista, Facundo D.

doi:10.1016/j.immuni.2008.04.007

Cited by 145 publications

(107 citation statements)

References 123 publications

(135 reference statements)

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“…It is unclear why CD19 is required for IDO induction after TLR9 ligation in vivo. CD19 regulates intracellular TLR signaling in B cells, lowers B-cell activation thresholds, and is required for optimal B-cell responses to membrane-bound antigens (25)(26)(27)(28). Thus, CD19 may transduce intracellular signals from TLR9 in IDO-competent cells.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, like DCs-but unlike resting B cells-IDO-competent cells were potent T-cell APCs when not induced to express IDO, confirming that IDOcompetent cells are a distinct cell subtype with attributes of B cells and DCs. CD19 amplifies B cell receptor (BCR) signaling and promotes Bcell responses to membrane-bound antigens (25)(26)(27)(28). We hypothesized that CD19 is required for IDO induction in DCs.…”

Section: B Cells | T-cell Regulation | Cd19mentioning

confidence: 99%

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B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase

Johnson¹,

Kahler²,

Baban³

et al. 2010

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

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A discrete population of splenocytes with attributes of dendritic cells (DCs) and coexpressing the B-cell marker CD19 is uniquely competent to express the T-cell regulatory enzyme indoleamine 2,3-dioxygenase (IDO) in mice treated with TLR9 ligands (CpGs). Here we show that IDO-competent cells express the B-lineage commitment factor Pax5 and surface immunoglobulins. CD19 ablation abrogated IDO-dependent T-cell suppression by DCs, even though cells with phenotypic attributes matching IDO-competent cells developed normally and expressed IDO in response to interferon γ. Consequently, DCs and regulatory T cells (Tregs) did not acquire T-cell regulatory functions after TLR9 ligation, providing an alternative perspective on the known T-cell regulatory defects of CD19-deficient mice. DCs from B-cell-deficient mice expressed IDO and mediated T-cell suppression after TLR9 ligation, indicating that B-cell attributes were not essential for B-lymphoid IDO-competent cells to regulate T cells. Thus, IDO-competent cells constitute a distinctive B-lymphoid cell type with quintessential T-cell regulatory attributes and phenotypic features of both B cells and DCs. B cells | T-cell regulation | CD19I ndoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme expressed in response to interferons (IFNs) at sites of inflammation. IDO inhibitors exacerbated T-cell-mediated pathology in models of tumor growth and autoimmune, infectious, and allergic diseases, and are currently under evaluation as potential tumor vaccine adjuvants in clinical settings (1, 2). By analogy to the tumor-protective effects of IDO, some pathogens may exploit IDO to facilitate persistence and IDO may attenuate vaccine-induced immunity (3-6). Consistent with this paradigm, artificially enhanced IDO activity attenuated graft versus host disease after bone marrow engraftment and prolonged rat lung allograft survival (7-9). Thus, IDO-dependent T-cell regulation occurs in multiple settings of chronic inflammation relevant to clinical syndromes.Despite the potential benefits of manipulating IDO activity to improve therapy in chronic inflammatory syndromes, little is known about the cellular basis of IDO-mediated T-cell regulation in physiologic settings. Antigen presenting cells (APCs) expressing IDO, such as dendritic cells (DCs), activate regulatory T cells (Tregs) and directly suppress effector T cells at sites of tissue inflammation (10, 11). Cells with functional and phenotypic attributes of DCs in mice and humans are competent to express IDO and regulate T-cell responses (11-15). In mice, splenocytes uniquely competent to mediate T-cell suppression via IDO after in vivo treatment with TLR9 ligands (CpGs) were a rare cell type located in splenic red pulp with phenotypic attributes of DCs (CD11c, CD8α, CD80/86, MHCII). IDO-competent cells also expressed B220 and the B-cell lineage marker CD19, but not the plasmacytoid DC (pDC) marker PDCA/120G8 (13). After CTLA4-Ig and CpG treatment, IDO-competent cells produced IFNα (15, 16), a functional attribute of pDCs and ...

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Section: Discussionmentioning

confidence: 99%

Section: B Cells | T-cell Regulation | Cd19mentioning

confidence: 99%

B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase

Johnson¹,

Kahler²,

Baban³

et al. 2010

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

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“…Noncovalent binding of traditional antigens to Ab CDRs expressed within the BCR complex activates signal-transducing proteins (Ig␣, Ig␤, CD19, CD22, and Lyn) by an allosteric mechanism, thereby driving the initial recruitment of individual B cell clones and their adaptive differentiation into Ab-secreting plasma cells (80). The 421-433 CD4BS region, however, is a B cell SAg epitope for which preimmune human BCRs and secreted Abs produced without exposure to gp120 already express a binding site encoded by V H germ line genes without a requirement for adaptive sequence diversification (7,10,11,13,71).…”

Section: Discussionmentioning

confidence: 99%

Toward Effective HIV Vaccination

Nishiyama

Planque

Mitsuda

et al. 2009

Journal of Biological Chemistry

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We describe murine monoclonal antibodies (mAbs) raised by immunization with an electrophilic gp120 analog (E-gp120) expressing the rare ability to neutralize genetically heterologous human immunodeficiency virus (HIV) strains. Unlike gp120, E-gp120 formed covalent oligomers. The reactivity of gp120 and E-gp120 with mAbs to reference neutralizing epitopes was markedly different, indicating their divergent structures. Epitope mapping with synthetic peptides and electrophilic peptide analogs indicated binary recognition of two distinct gp120 regions by anti-E-gp120 mAbs, the 421-433 and 288 -306 peptide regions. Univalent Fab and single chain Fv fragments expressed the ability to recognize both peptides. X-ray crystallography of an anti-E-gp120 Fab fragment revealed two neighboring cavities, the typical antigen-binding cavity formed by the complementarity determining regions (CDRs) and another cavity dominated by antibody heavy chain variable (V H ) domain framework (FR) residues. Substitution of the FR cavity V H Lys-19 residue by an Ala residue resulted in attenuated binding of the 421-433 region peptide probe. The CDRs and V H FR replacement/silent mutation ratios exceeded the ratio for a random mutation process, suggesting adaptive development of both putative binding sites. All mAbs studied were derived from V H 1 family genes, suggesting biased recruitment of the V gene germ line repertoire by E-gp120. The conserved 421-433 region of gp120 is essential for HIV binding to host CD4 receptors. This region is recognized weakly by the FR of antibodies produced without exposure to HIV, but it usually fails to induce adaptive synthesis of neutralizing antibodies. We present models accounting for improved CD4-binding site recognition and broad HIV neutralizing activity of the mAbs, long sought goals in HIV vaccine development.

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“…This is the result of a complex process of differentiation that starts when B cells encounter Ag through engagement with the B cell Ag receptor that mediates the internalization, processing, and presentation of Ags to T cells, an important requirement for a successful immune response (1,2). This engagement initiates a signaling cascade leading to B cell activation (3), which takes place after either T cell-dependent orindependent pathways.…”

mentioning

confidence: 99%

Binding of HLA-G to ITIM-Bearing Ig-like Transcript 2 Receptor Suppresses B Cell Responses

Naji

Menier

Morandi

et al. 2014

The Journal of Immunology

145

123

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Inhibition of B cells constitutes a rational approach for treating B cell–mediated disorders. We demonstrate in this article that the engagement of the surface Ig-like transcript 2 (ILT2) inhibitory receptor with its preferential ligand HLA-G is critical to inhibit B cell functions. Indeed, ILT2–HLA-G interaction impedes both naive and memory B cell functions in vitro and in vivo. Particularly, HLA-G inhibits B cell proliferation, differentiation, and Ig secretion in both T cell–dependent and –independent models of B cell activation. HLA-G mediates phenotypic and functional downregulation of CXCR4 and CXCR5 chemokine receptors on germinal center B cells. In-depth analysis of the molecular mechanisms mediated by ILT2–HLA-G interaction showed a G0/G1 cell cycle arrest through dephosphorylation of AKT, GSK-3β, c-Raf, and Foxo proteins. Crucially, we provide in vivo evidence that HLA-G acts as a negative B cell regulator in modulating B cell Ab secretion in a xenograft mouse model. This B cell regulatory mechanism involving ILT2–HLA-G interaction brings important insight to design future B cell–targeted therapies aimed at reducing inappropriate immune reaction in allotransplantation and autoimmune diseases.

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New Insights into the Early Molecular Events Underlying B Cell Activation

Cited by 145 publications

References 123 publications

B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase

B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase

Toward Effective HIV Vaccination

Binding of HLA-G to ITIM-Bearing Ig-like Transcript 2 Receptor Suppresses B Cell Responses

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