Cross-linking of OX40 ligand, a member of the TNF/NGF cytokine family, induces proliferation and differentiation in murine splenic B cells.
OX40 is a member of the TNF/NGF-receptor family expressed on activated T cells, whose ligand is found on activated T and B cells. In the present study, we show that cross-linking of OX40L on CD40L-stimulated B cells, alpha IgD dextran-stimulated B cells, or both results in a significantly enhanced proliferative response with no change in the cell survival rate. Furthermore, OX40 stimulation increases immunoglobulin heavy chain mRNA levels and immunoglobulin secretion, which could not be blocked by anti-cytokine antibodies. In additional molecular studies, we show that OX40L cross-linking results in the down-regulation of the transcription factor BSAP. This, in turn, leads to a change in the in vivo binding pattern of the immunoglobulin heavy chain gene 3' alpha enhancer, suggesting its activation. This effect may thus be one mechanism for OX40-induced increase in immunoglobulin secretion. In conclusion, our data suggest that the OX40-OX40L interaction is a novel pathway in T cell-dependent B cell proliferation and differentiation.
Stüber
E
E
Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Neurath
M
M
Calderhead
D
D
Fell
H P
HP
Strober
W
W
D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000502:physiology*; D001483:Base Sequence; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D015870:Gene Expression; D007132:Immunoglobulin Isotypes / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D053278:OX40 Ligand; D015345:Oligonucleotide Probes / Q000737:chemistry; D051757:PAX5 Transcription Factor; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012333:RNA, Messenger / Q000235:genetics; D011940:Receptor Aggregation; D018121:Receptors, Cytokine / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D012097:Repressor Proteins; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D014157:Transcription Factors / Q000378:metabolism; D048069:Tumor Necrosis Factors; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D007132:Immunoglobulin Isotypes; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; D053278:OX40 Ligand; D015345:Oligonucleotide Probes; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; C513258:Prdm1 protein, mouse; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D018124:Receptors, Tumor Necrosis Factor; D012097:Repressor Proteins; C504586:Tnfsf4 protein, mouse; D014157:Transcription Factors; D048069:Tumor Necrosis Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1