CD72 down-modulates BCR-induced signal transduction and diminishes survival in primary mature B lymphocytes.
CD72, a 45-kDa type II transmembrane glycoprotein carrying an ITIM motif, is believed to be an inhibitory coreceptor of the BCR. Mature B cells lacking CD72 show enhanced Ca(2+) mobilization and are hyperproliferative in response to BCR ligation. However, the signal transduction pathways downstream of BCR signaling that transmit the inhibitory effect of CD72 in mature B cells remain unknown. To address this question, we used hen egg lysozyme-specific BCR transgenic mice to elucidate the differential cell signaling between wild-type and CD72-deficient B cells in response to hen egg lysozyme Ag stimulation. Our results demonstrate that CD72 predominantly down-regulates the major signal transduction pathways downstream of the BCR, including NF-AT, NF-kappaB, ERK, JNK, p38-MAPK, and PI3K/Akt in mature B cells. CD72 ligation with anti-CD72 Ab (K10.6), which mimics the binding of CD100 (a natural ligand for CD72) to release the inhibitory function of CD72, augments cell proliferation, Ca(2+) flux, IkappaBalpha activation, and ERK MAPK activity upon Ag stimulation in wild-type B cells. In addition, we show direct evidence that CD72 promotes cell cycle arrest and apoptosis after Ag stimulation in mature B cells. Taken together, our findings conclude that CD72 plays a dominant role as a negative regulator of BCR signaling in primary mature B lymphocytes.
Li
Daniel H
DH
Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA 94305, USA.
Tung
James W
JW
Tarner
Ingo H
IH
Snow
Andrew L
AL
Yukinari
Tsuyoshi
T
Ngernmaneepothong
Rachel
R
Martinez
Olivia M
OM
Parnes
Jane R
JR
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes; D015415:Biomarkers; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D015536:Down-Regulation; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009113:Muramidase / Q000494:pharmacology; D050778:NFATC Transcription Factors / Q000378:metabolism; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism
D015703:Antigens, CD; D015415:Biomarkers; D050778:NFATC Transcription Factors; D011947:Receptors, Antigen, B-Cell; D051996:Transcription Factor RelA; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D020928:Mitogen-Activated Protein Kinases; D009113:Muramidase; D002118:Calcium