Peritoneal CD5+ B-1 cells have signaling properties similar to tolerant B cells.
CD5(+) B (or B-1) cells are the normal precursors of B cell chronic lymphocytic leukemia. They differ from conventional B (B-2) cells with respect to their phenotype and mitogenic responses and are often secretors of the natural polyreactive antibodies in the serum. The origin of B-1 cells remains controversial, and the relationship between B-1 cells and autoreactive B cells is unclear. Here, we compare the signaling pathways that are activated by the engagement of the B cell antigen receptor (BCR) in B-1 and B-2 cells. Stimulation of the BCR leads to the induced activation of the three major classes of mitogen-activated protein kinases (MAPKs), ERK, JNK, and p38 MAPK, as well as the Akt kinase and the transcription factors nuclear factor of activated T cells (NF-AT) and NF-kappaB in B-2 cells. In contrast, B-1 cells have constitutive activation of ERK and NF-AT but exhibit delayed JNK and lack p38 MAPK and NF-kappaB induction upon BCR cross-linking. The lack of NF-kappaB activation in B-1 cells may be due to a lack of Akt activation in these cells. Furthermore, our study using specific inhibitors reveals that the extended survival of B-1 cells in culture is not due to the constitutive activation of ERK; nor is it due to Akt signaling or Bcl-x(L) up-regulation, since these are not induced in B-1 cells. The current findings of altered MAPK and NF-AT activation and lack of NF-kappaB induction in B-1 cells indicate that these cells have signaling properties similar to tolerant B cells that are chronically exposed to self-antigens. Indeed, BCR stimulation of B-1 cells does not lead to their full activation as indicated by their lack of maximal up-regulation of specific markers such as CD25, CD69, and CD86.
Wong
Siew-Cheng
SC
Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117609, Singapore.
Chew
Weng-Keong
WK
Tan
Joy En-Lin
JE
Melendez
Alirio J
AJ
Francis
Florence
F
Lam
Kong-Peng
KP
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D018956:CD5 Antigens / Q000032:analysis*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D007108:Immune Tolerance; D007075:Immunoglobulin M / Q000502:physiology; D007135:Immunoglobulin Variable Region / Q000032:analysis; D007527:Isoenzymes / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D051966:Phospholipase C gamma; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
D018956:CD5 Antigens; D004268:DNA-Binding Proteins; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D007527:Isoenzymes; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011947:Receptors, Antigen, B-Cell; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma