Background and Objectives Follicular helper T (Tfh) cells are instrumental in the development of humoral responses. They support the terminal differentiation of B cells into memory and antibody-producing cells within germinal centers. Regulatory B (Breg) cells can modulate inflammatory reactions through the control of dendritic cell maturation and function, and through the control of T cell proliferation and Th1 polarization. Our aimed was to evaluate the control of humoral responses by Breg cells.
Materials and Methods We developed in vitro models of human Tfh cell polarisation and function. They were obtained by stimulation of purified T cells with anti-CD3 and anti-CD28 Abs in the presence of IL-12 and IL-21. Expression of Bcl-6, IL-21, ICOS, CXCR5 and PD-1, all characteristics of Tfh cells were determined by flow cytometry. Tfh functions were studied by co-cultures with non-stimulated purified B cells. Their differentiation into memory and plasma cells was appraised by flow cytometry and by ELISA to measure the production of immunolgobulins. Breg cells were obtained by stimulation of purified B cells with CpG-ODN on CD40L-transfected fibroblasts. Their effect on Tfh cell maturation and function were studied in co-culture experiments.
Results in vitro Tfh cells were obtained. Thus, Bcl-6 was up-regulated, IL-21 induced and ICOS, CXCR5 and PD-1 expression increased after stimulation. Furthermore, differentiated Tfh cells fostered the maturation of IgD-CD27 + memory B cells and CD138 + plasma cells, and triggered the secretion of IgM, IgG and IgA. Added to the T cells, Breg cells restrained the expression of Tfh markers. In the co-cultures of Tfh with B cells, Breg cells inhibited the induction of IgD-CD27 + and CD138 + B cells. They also impeded the secretion of immunoglobulins. Using blocking antibodies, suppressive activities of Bregs were found to be dependent on IL-10 and TGFbeta and based on direct contact with Tfh cells involving CD40, CD80, CD86 and CD54 molecules.
Conclusions Human Breg cells can modulate the development of humoral responses through the control of Tfh cell polarization and of Tfh-dependent terminal differentiation of B cells. Whether these properties are impaired and responsible for abnormal humoral responses in autoimmune diseases needs now to be established.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.