TY - JOUR
T1 - Transmembrane activator, calcium modulator, and cyclophilin ligand interactor drives plasma cell differentiation in LPS-activated B cells
AU - Ozcan, Esra
AU - Garibyan, Lilit
AU - Lee, John Jhe Yun
AU - Bram, Richard J.
AU - Lam, Kong Peng
AU - Geha, Raif S.
N1 - Funding Information:
Supported by March of Dimes grant no. 6-FY07-285 and National Institutes of Health grant AI-031541.
PY - 2009/6
Y1 - 2009/6
N2 - Background: Transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI) expression on B cells is upregulated by Toll-like receptor (TLR) 4. Objective: We sought to examine whether TACI synergizes with TLR4 in driving immunoglobulin production by B cells and to examine the mechanism of this synergy. Methods: Purified mouse naive B cells were stimulated with the TACI ligand a proliferation-inducing ligand (APRIL) and with suboptimal concentrations of the TLR4 ligand LPS in the presence or absence of IL-4. Immunoglobulin secretion was measured by means of ELISA. Surface IgG1-positive B cells and CD138+ plasmacytoid cells were enumerated by means of FACS. Expression of γ1 and ε{lunate} germline transcripts, activation-induced cytidine deaminase, and γ1 and ε{lunate} mature transcripts was measured by means of RT-PCR. Results: APRIL synergized with LPS in driving B-cell proliferation and IgM, IgG1, IgG3, IgE, and IgA production. This was mediated by TACI because it was preserved in B-cell maturation antigen-/-, but not TACI-/-, B cells. APRIL and LPS synergized to promote isotype switching, as evidenced by increased expression of activation-induced cytidine deaminase and γ1 and ε{lunate} mature transcripts and generation of surface IgG1-positive cells. More importantly, APRIL and LPS strongly synergized to drive the plasma cell differentiation program, as evidenced by an increase in CD138+ cells and expression of B lymphocyte induced maturation protein-1 (Blimp-1), interferon regulatory factor-4 (IRF-4), and the spliced form of X-box binding protein-1 (XBP-1). TACI-/- mice had impaired IgM and IgG1 antibody responses to immunization, with a suboptimal dose of the type I T cell-independent antigen 2, 4, 6- Trinitrophenol (TNP)-LPS. Conclusions: These observations suggest that TACI cooperates with TLR4 to drive B-cell differentiation and immunoglobulin production in vitro and in vivo.
AB - Background: Transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI) expression on B cells is upregulated by Toll-like receptor (TLR) 4. Objective: We sought to examine whether TACI synergizes with TLR4 in driving immunoglobulin production by B cells and to examine the mechanism of this synergy. Methods: Purified mouse naive B cells were stimulated with the TACI ligand a proliferation-inducing ligand (APRIL) and with suboptimal concentrations of the TLR4 ligand LPS in the presence or absence of IL-4. Immunoglobulin secretion was measured by means of ELISA. Surface IgG1-positive B cells and CD138+ plasmacytoid cells were enumerated by means of FACS. Expression of γ1 and ε{lunate} germline transcripts, activation-induced cytidine deaminase, and γ1 and ε{lunate} mature transcripts was measured by means of RT-PCR. Results: APRIL synergized with LPS in driving B-cell proliferation and IgM, IgG1, IgG3, IgE, and IgA production. This was mediated by TACI because it was preserved in B-cell maturation antigen-/-, but not TACI-/-, B cells. APRIL and LPS synergized to promote isotype switching, as evidenced by increased expression of activation-induced cytidine deaminase and γ1 and ε{lunate} mature transcripts and generation of surface IgG1-positive cells. More importantly, APRIL and LPS strongly synergized to drive the plasma cell differentiation program, as evidenced by an increase in CD138+ cells and expression of B lymphocyte induced maturation protein-1 (Blimp-1), interferon regulatory factor-4 (IRF-4), and the spliced form of X-box binding protein-1 (XBP-1). TACI-/- mice had impaired IgM and IgG1 antibody responses to immunization, with a suboptimal dose of the type I T cell-independent antigen 2, 4, 6- Trinitrophenol (TNP)-LPS. Conclusions: These observations suggest that TACI cooperates with TLR4 to drive B-cell differentiation and immunoglobulin production in vitro and in vivo.
KW - B cells
KW - LPS
KW - Toll-like receptor
KW - a proliferation-inducing ligand
KW - immunoglobulin
KW - transmembrane activator, calcium modulator, and cyclophilin ligand interactor
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U2 - 10.1016/j.jaci.2009.03.019
DO - 10.1016/j.jaci.2009.03.019
M3 - Article
C2 - 19427685
AN - SCOPUS:67649172968
SN - 0091-6749
VL - 123
SP - 1277-1286.e5
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 6
ER -