Achouak Achour1, Quentin Simon1, Audrey Mohr1, Jean-François Séité2, Pierre Youinou2, Boutahar Bendaoud3, Ibtissem Ghedira4, Jacques-Olivier Pers2, Christophe Jamin5. 1. Université de Brest, INSERM U1227, Lymphocytes B et Autoimmunité, and LabEx IGO, Brest, France. 2. Université de Brest, INSERM U1227, Lymphocytes B et Autoimmunité, and LabEx IGO, Brest, France; CHRU Morvan, Laboratoire d'Immunologie, Brest, France. 3. CHRU Morvan, Laboratoire d'Immunologie, Brest, France. 4. Faculty of Pharmacy, Department of Immunology, Research Unit (03/UR/07-02), Monastir, Tunisia. 5. Université de Brest, INSERM U1227, Lymphocytes B et Autoimmunité, and LabEx IGO, Brest, France; CHRU Morvan, Laboratoire d'Immunologie, Brest, France. Electronic address: christophe.jamin@univ-brest.fr.
Abstract
BACKGROUND: Follicular helper T (TFH) cells support terminal B-cell differentiation. Human regulatory B (Breg) cells modulate cellular responses, but their control of TFH cell-dependent humoral immune responses is unknown. OBJECTIVE: We sought to assess the role of Breg cells on TFH cell development and function. METHODS: Human T cells were polyclonally stimulated in the presence of IL-12 and IL-21 to generate TFH 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. RESULTS: 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 TFH 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 TFH cell development. Added to TFH 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 TFH 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. CONCLUSION: Human Breg cells control TFH cell maturation, expand follicular regulatory T cells, and inhibit the TFH 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 TFH cell-dependent control of humoral immunity and might lead to the development of aberrant autoimmune responses.
BACKGROUND:Follicular helper T (TFH) cells support terminal B-cell differentiation. Human regulatory B (Breg) cells modulate cellular responses, but their control of TFH cell-dependent humoral immune responses is unknown. OBJECTIVE: We sought to assess the role of Breg cells on TFH cell development and function. METHODS:Human T cells were polyclonally stimulated in the presence of IL-12 and IL-21 to generate TFH 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. RESULTS: 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 TFH 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 TFH cell development. Added to TFH 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 TFH 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. CONCLUSION:Human Breg cells control TFH cell maturation, expand follicular regulatory T cells, and inhibit the TFH 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 TFH cell-dependent control of humoral immunity and might lead to the development of aberrant autoimmune responses.
Authors: Qiang Fu; Kang Mi Lee; Guoli Huai; Kevin Deng; Divyansh Agarwal; Charles G Rickert; Noel Feeney; Rudy Matheson; Hongji Yang; Christian LeGuern; Shaoping Deng; James F Markmann Journal: Am J Transplant Date: 2021-09-06 Impact factor: 8.086