Human regulatory B cells control the T_FH cell response.

Abstract

Follicular helper T (T_FH) cells support terminal B-cell differentiation. Human regulatory B (Breg) cells modulate cellular responses, but their control of T_FH cell-dependent humoral immune responses is unknown. We sought to assess the role of Breg cells on T_FH cell development and function. Human T cells were polyclonally stimulated in the presence of IL-12 and IL-21 to generate T_FH cells. They were cocultured with B cells to induce their terminal differentiation. Breg cells were included in these cultures, and their effects were evaluated by using flow cytometry and ELISA. B-cell lymphoma 6, IL-21, inducible costimulator, CXCR5, and programmed cell death protein 1 (PD-1) expressions increased on stimulated human T cells, characterizing T_FH cell maturation. In cocultures they differentiated B cells into CD138⁺ plasma and IgD^-CD27⁺ memory cells and triggered immunoglobulin secretions. Breg cells obtained by Toll-like receptor 9 and CD40 activation of B cells prevented T_FH cell development. Added to T_FH cell and B-cell cocultures, they inhibited B-cell differentiation, impeded immunoglobulin secretions, and expanded Foxp3⁺CXCR5⁺PD-1⁺ follicular regulatory T cells. Breg cells modulated IL-21 receptor expressions on T_FH cells and B cells, and their suppressive activities involved CD40, CD80, CD86, and intercellular adhesion molecule interactions and required production of IL-10 and TGF-β. Human Breg cells control T_FH cell maturation, expand follicular regulatory T cells, and inhibit the T_FH cell-mediated antibody secretion. These novel observations demonstrate a role for the Breg cell in germinal center reactions and suggest that deficient activities might impair the T_FH cell-dependent control of humoral immunity and might lead to the development of aberrant autoimmune responses.