Transmembrane activator, calcium modulator, and cyclophilin ligand interactor drives plasma cell differentiation in LPS-activated B cells.
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 gamma1 and epsilon germline transcripts, activation-induced cytidine deaminase, and gamma1 and epsilon 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 gamma1 and epsilon 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.
Division of Immunology, Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Esra
E
Ozcan
Lilit
L
Garibyan
John Jhe-Yun
JJ
Lee
Richard J
RJ
Bram
Kong-Peng
KP
Lam
Raif S
RS
Geha
D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D053301:B-Cell Maturation Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D007136:Immunoglobulins / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology; D008024:Ligands; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000378:metabolism*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000494:pharmacology*
D053301:B-Cell Maturation Antigen; D007136:Immunoglobulins; D008024:Ligands; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; C486361:Tnfrsf13b protein, mouse; C491959:Tnfsf13 protein, mouse; D051197:Toll-Like Receptor 4; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; C048761:trinitrophenyl-lipopolysaccharide; D015847:Interleukin-4