Antigens Varying in Affinity for the B Cell Receptor Induce Differential B Lymphocyte Responses

Spontaneous CD8+ T cell activation in MRL-Faslpr mice is B cell dependent. It is unclear whether this B-dependent activation is mediated by direct Ag presentation via MHC class I proteins (i.e., cross-presentation) or whether activation occurs by an indirect mechanism, e.g., via effects on CD4+ cells. To determine how CD8+ T cell activation is promoted by B cells, we created mixed bone marrow chimeras where direct MHC class I Ag presentation by B cells was abrogated while other leukocyte compartments could express MHC class I. Surprisingly, despite the absence of B cell class I-restricted Ag presentation, CD8+ T cell activation was intact in the chimeric mice. Therefore, the spontaneous B cell-dependent CD8+ T cell activation that occurs in systemic autoimmunity is not due to direct presentation by B cells to CD8+ T cells.

Section: Discussionmentioning

confidence: 99%

Cutting Edge: B Cells Promote CD8+ T Cell Activation in MRL-FaslprMice Independently of MHC Class I Antigen Presentation

Chan¹,

Shlomchik

2000

“…This lends credence to our own argument, made above, that differences in the kinetics of Ag association by B cells may variably modulate intracellular signaling. Indeed, in their study, Kouskoff et al have noted that the correlation between response and affinity of BCR for Ag was not perfect (49). They have consequently suggested that, rather than equilibrium affinity, the kinetics of BCR-ligand interaction may constitute the principal determinant of the outcome of activation responses (49).…”

Section: Discussionmentioning

confidence: 99%

“…That the BCR is in fact susceptible to Ag-regulated differential signaling has been recently demonstrated, albeit for T-independent responses (49). Using a panel of M13-phage-displayed peptide ligands with varying affinities for B cells bearing a transgenic sIg receptor, Kouskoff et al (49) reported that BCR-mediated activation, as judged by a variety of parameters, is variably influenced by the affinity of Ag for BCR.…”

Section: Discussionmentioning

confidence: 99%

“…Using a panel of M13-phage-displayed peptide ligands with varying affinities for B cells bearing a transgenic sIg receptor, Kouskoff et al (49) reported that BCR-mediated activation, as judged by a variety of parameters, is variably influenced by the affinity of Ag for BCR. Indeed some, but not all, of the early BCR-dependent signaling such as Ca 2ϩ mobilization and tyrosine phosphorylation of Syk and IgA, but not Lyn, were highly dependent on affinity of BCR for peptide (49). These latter results are particularly significant in the present context.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

B Cell Responses to a Peptide Epitope. IX. The Kinetics of Antigen Binding Differentially Regulates Costimulatory Capacity of Activated B Cells

Vijayakrishnan

Natarajan

Manivel

et al. 2000

We explore the possible mechanism by which association rates of Ag with activated B cells influences the ability of the latter to selectively recruit Th subsets. Our system used cocultures of Ag-activated B and T cells, where the Ag was a synthetic peptide, G41CT3. Restimulation was with either peptide G41CT3 or its analogue, G28CT3. Peptide G28CT3 has been previously shown to display a higher on rate, relative to the homologous peptide G41CT3, of binding to G41CT3-activated B cells. This difference in on rates was eventually exerted at the level of IFN-γ, but not of IL-10, induction from T cells, with peptide G28CT3 proving more effective. However, various treatment regimens rendered peptide G41CT3 as potent as peptide G28CT3 at eliciting IFN-γ responses from the above cultures. This included simultaneous treatment of B cells with peptide G41CT3 and the protein tyrosine kinase inhibitor tyrphostin. Alternatively, pretreatment of B cells with a peptide representing only the B cell epitope constituent of peptide G28CT3 (G28) was also equally effective. Subsequent experiments revealed that IFN-γ production from activated T cells resulted from an engagement of CD28 by B7-1 on the B cell surface. Finally, the extent of cell surface B7-1 up-regulation on activated B cells was dependent on the on rate of Ag binding to the membrane-bound Ig receptor. Thus, cumulative results suggest that the kinetics of Ag binding to activated B cells can differentially regulate intracellular signaling. This influences selective costimulatory molecule expression, with its consequent effects on relative Th subset activation.

“…Thus, the apparent similarity of affinity between group I and group II precursors for NPPC may not fully reflect the affinity of group II B cells for the carrier determinants present on the selecting ligand. In addition, the selective forces in vivo are likely to be complex as the B cell receptor is sensitive to binding kinetics (k on and k off ), avidity, and epitope density and organization (47)(48)(49)(50)(51)(52). Clearly, group II Abs develop higher affinity binding for the PC carrier as recurrent mutations can increase the affinity for the PC-protein complex up to 1000-fold greater than T15 (32,53).…”

Section: Why Do T15 Id ϩ B Cells Enter Germinal Centers During the Prmentioning

confidence: 99%

Repertoire Shift in the Humoral Response to Phosphocholine-Keyhole Limpet Hemocyanin: VH Somatic Mutation in Germinal Center B Cells Impairs T15 Ig Function

Wiens

Brown

Rittenberg

2003

Phosphocholine (PC) is a naturally occurring Ag common to many pathogenic microorganisms. Early in the primary response to PC conjugated to keyhole limpet hemocyanin (KLH), T15 Id+ Abs constitute >90% of the serum Ig in BALB/c mice. During the late primary and memory response to PC-protein, a shift in the repertoire occurs and T15 Id+ Abs lose dominance. In this study, we use immunohistochemistry and single germinal center microdissection to locate T15 Id+ cells in the spleen in a primary response to PC-KLH. We demonstrate T15 Id+ B cells and VH1-DFL16.1-JH1 and Vκ22-Jκ5 rearrangements in germinal centers early in the immune response; thus loss of T15 dominance is not due to lack of T15 cells within germinal centers. One-hundred thirty one VH1 and 57 Vκ22 rearrangements were cloned and sequenced. Thirty four percent of the VH1 clones and 37% of the Vκ22 clones contained somatic mutations indicating participation in the germinal center response. Six variant T15 H clones were expressed with wild-type T15 L chain in vitro. Two of these Abs were defective in secretion providing the first evidence that mutation occurring in vivo can disrupt Ig assembly and secretion. Of the four secretion-competent Abs, two failed to display binding to PC-protein, while the other two displayed altered carrier recognition. These results indicate that somatic mutation of T15 in vivo can result in the loss of binding and secretion, potentially leading to B cell wastage. The failure of T15 to gain affinity enhancing mutations in the face of these detrimental changes may contribute to repertoire shift.