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Published on: June 2, 2010
A role for the VLA-4 integrin in the activation of human memory B cells
A Silvy1, P Altevogt, P Mondière
1INSERM U 404, Immunité et Vaccination, Lyon, France.
Insights
Human memory B cells can be activated by cytokines alone at high cell density, independent of CD40 or B cell receptor (BCR) engagement. This activation relies on VLA-4 interactions, suggesting a novel co-stimulatory pathway for B cell responses.
Area of Science:
- Immunology
- Cell Biology
Background:
- B cell activation typically requires co-stimulatory signals from molecules like CD40 or the B cell receptor (BCR) alongside cytokines for proliferation and antibody secretion.
- The precise mechanisms driving B cell activation, particularly under conditions of high cell density, are not fully elucidated.
Purpose of the Study:
- To investigate whether B cells can be directly stimulated by cytokines without conventional co-stimulation.
- To identify the molecular interactions involved in cytokine-mediated B cell activation at high cell density.
- To determine which B cell subsets are responsive to this novel activation pathway.
Main Methods:
- Purified human tonsillar B cells were cultured at high cell density and stimulated with a cytokine combination.
- The role of cell-cell contact was assessed using anti-very late antigen (VLA)-4 monoclonal antibodies and an LDV-containing peptide.
- B cell proliferation and immunoglobulin secretion were measured.
- Flow cytometry was used to analyze VLA-4 expression on different B cell subsets.
Main Results:
- High-density B cell cultures stimulated with cytokines alone induced proliferation and immunoglobulin secretion.
- Inhibition of VLA-4 (very late antigen-4) with antibodies or peptides significantly suppressed this cytokine-driven activation.
- VLA-4 blockade also reduced B cell responses to B cell receptor (BCR) and CD40 engagement.
- Only memory B cells, not virgin or germinal center B cells, responded to direct cytokine stimulation.
- Dual expression of VLA-4 alpha and beta chains was characteristic of memory B cells.
Conclusions:
- VLA-4-dependent homotypic B cell interactions provide a co-stimulatory signal to human memory B cells.
- This pathway can mediate B cell activation independently of CD40 or BCR engagement under specific conditions.
- VLA-4 plays a crucial role in both direct cytokine-driven B cell activation and conventional BCR/CD40-mediated responses.
Abstract:
It is generally recognized that activation through membrane effector molecules such as CD40 or the B cell receptor (BCR) is mandatory to allow B cells to proliferate and differentiate into antibody (Ab)-secreting cells in response to cytokines. We show here that purified tonsillar B cells can be stimulated directly by a cytokine combination to proliferate and secrete immunoglobulins when cultures are performed at high cell density. The contact-mediated activation of B cells in this experimental system is strongly inhibited both by anti-very late antigen (VLA)-4 monoclonal Ab and by a peptide containing the LDV sequence specifically recognized by the alpha 4 integrin binding site. These reagents also significantly suppressed the B cell responses elicited by engagement of the BCR or CD40. Our data reveal that memory B cells but not virgin or germinal center B cells are sensitive to the direct stimulatory effect of cytokines in high-density cultures. Finally, we found that the dual expression of the alpha and beta chains of VLA-4 is a distinctive feature of the memory B cell population. Collectively, our findings support the notion that VLA-4-dependent homotypic B cell interactions can mediate a co-stimulatory signal to human memory B cells and might participate in the B cell activation triggered through the BCR and CD40.
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