Peritoneal CD5+ B-1 Cells Have Signaling Properties Similar to Tolerant B Cells

doi:10.1074/jbc.M202460200

Peritoneal CD5⁺ B-1 Cells Have Signaling Properties Similar to Tolerant B Cells*

From the ^‡Institute of Molecular and Cell Biology, 30 Medical Dr., Singapore 117609, Singapore and the ^§Department of Physiology, Faculty of Medicine, National University of Singapore, Singapore 117597, Singapore

Abstract

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-κB 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-κB induction upon BCR cross-linking. The lack of NF-κB 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-κB 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.

Footnotes

↵* This work is supported by grants from the Biomedical Research Council of the Agency for Science, Technology, and Research.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¶ To whom correspondence should be addressed. Tel.: 65-6874-3784; Fax: 65-6779-1117; E-mail: mcblamkp@imcb.nus.edu.sg.
Published, JBC Papers in Press, June 17, 2002, DOI 10.1074/jbc.M202460200
Abbreviations:

B-CLL

B-cell chronic lymphocytic leukemia

Ab

antibody

BCR

B cell antigen receptor

ERK

extracellular signal-regulated kinase

IP₃

inositol 1,4,5-triphosphate

JNK

c-Jun NH₂-terminal kinase

LPS

lipopolysaccharide

MAPK

mitogen-activated protein kinases

NF-AT

nuclear factor of activated T cells

PI(4

5)P₂, phosphatidylinositol 4,5-bisphosphate

PMA

phorbol 12-myristate 13-acetate

PLC

phospholipase C

FACS

fluorescence-activated cell sorting

Btk

Bruton's tyrosine kinase
- Received March 14, 2002.
- Revision received June 12, 2002.
The American Society for Biochemistry and Molecular Biology, Inc.