To the editor:
B cells are classically known for producing antibodies. However, several reports also indicate that B cells are potent regulators of immune responses including those mediated by dendritic cells (DCs), although direct effect of B cells on DC was relatively unexplored.1-4 Recently, Morva et al demonstrated that CD40 + TLR9 (CpG)–stimulated human B cells restrain the differentiation of monocyte-derived DCs and their maturation.5 They further found that stimulation of B cells is necessary to trigger potent regulatory activities on DCs.
Under physiological conditions, there is a constant cross-talk between DCs and B cells. Although suppression of DCs may play a role in preventing the autoimmunity, normal functioning of DCs without suppression is also critical for immune homeostasis and immune response to tumor cells and foreign antigens. These views indicate that B cells are not continually inhibitory on DCs. As B cells can receive activation signals via diverse receptors including B-cell receptor (BCR), CD40 and TLR, we surmised that the effect of stimulated B cells on DCs depends on the type of signals they receive. In view of the importance of BCR signaling in B-cell activation and in generation of regulatory B cells,1,2 we explored the role of BCR-stimulated B cells either alone or in combination with TLR9 stimulation on the differentiation and maturation of DC.
We found that when monocytes were differentiated into DCs in the presence of cytokines GM-CSF and IL-4 and B cells that were activated by combination of BCR + TLR9 (CpG) stimuli, there was a significant reduction in the expression of DC markers such as DC-SIGN, CD83, HLA-DR, CD40, CD80, CD86, and CD58 (Figure 1A). Thus, in accordance with Morva et al,5 our results revealed a regulatory role of BCR + CpG-stimulated B cells on differentiation of DCs. However, B cells that received signals only via BCR were not inhibitory (Figure 1A), indicating that in the absence of TLR stimuli, activated B cells do not block differentiation of DCs. In addition, we report a novel mechanism of modulation of DCs by regulatory B cells. We found that BCR + CpG-stimulated B cells induce a high percentage of apoptosis in differentiating DCs (Figure 1B). Thus, regulatory B cells can modulate DC-mediated immune responses by controlling the number of DCs. Of note, Fas-FasL–mediated apoptosis of target cells is proposed to be one of the mechanisms of immune regulation by regulatory B cells.1
Furthermore, compared with profound inhibition of LPS-mediated maturation of DCs by CD40 + CpG-activated B cells,5 we found that B cells that received BCR signaling alone were only partially inhibitory on DCs (Figure 1C). Together, our results indicate that regulation of DC differentiation and maturation by B cells depends on the type of stimuli they receive. B cells receiving BCR stimulation alone are not inhibitory on DCs while under inflammatory conditions as in TLR9 stimulation; these TLR-9–stimulated B cells can act as inflammation-limiting factors in part via inhibition of DC activation. These functional differences of B-cell stimuli were also reflected in their ability to induce the expression of key molecules CD62L and CD80/CD86 on B cells (Figure 1D) that are proposed to be important in the regulation of DC and T-cell functions, respectively, by regulatory B cells.5,6
Acknowledgments: This work was supported by Inserm, Center National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie, Université Paris Descartes and European Community's Seventh Framework Programme (FP7/2007-2013) under Grant Agreement No. 260338 ALLFUN.
Contribution: M.S.M. designed and performed the experiments, analyzed the data, and wrote the paper; S.V.K. analyzed the results and wrote the paper; and J.B. designed the experiments, analyzed the data, and wrote the paper.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Jagadeesh Bayry, Inserm Unité 872, Equipe 16–Centre de Recherche des Cordeliers, 15 rue de l'Ecole de Médicine, Paris, F-75006, France; e-mail: firstname.lastname@example.org.