The road to terminal B-cell differentiation
- James B Chung1
© Biomed Central Ltd 2001
Received: 9 August 2001
Accepted: 15 August 2001
Published: 16 August 2001
KeywordsB cell development plasma cells RAG-2 complementation system terminal differentiation transcription factor XBP-1 (X-box-binding protein-1)
Unlike early B cell development and activation, little is known about the factors that lead to the terminal differentiation of mature B lymphocytes to plasma cells. The authors previously found very high levels of X-box-binding protein-1 (XBP-1) transcripts in myeloma cell lines. In this study they sought to analyze the role of XBP-1 in the generation of plasma cells. Analysis is complicated by the fact that XBP-1-deficient mice die in utero, so the work was done using chimeric mice.
The authors found high levels of XBP-1 transcripts in plasma cells of rheumatoid synovium, and in purified B cells committed to plasma cell differentiation. B-cell lines transfected with XBP-1 possessed the surface phenotype of plasma cells. Lymphocytes deficient in XBP-1 failed to produce immunoglobulins in response to activating signals; this was reversed by transducing XBP-1 into the deficient B cells. The XBP-1-/- B cells had the same activation and proliferation profile as control B cells and showed evidence of class switching. Germinal centers formed normally after immunization but there was an absence of plasma cells and a dramatic decrease in immunoglobulin secretion. Interestingly the authors found an increase in the expression of c-Myc, which is usually downregulated as B cells exit the cell cycle. The authors conclude that XBP-1 is specifically required for progression of mature B cells to the plasma B-cell stage.
These data indicate that XBP-1 acts later than other transcription factors essential for germinal-center formation (e.g. Bcl-3, Bcl-6, nuclear factor-?B/p52 and interferon regulatory factor-4); however, the genes targeted by XBP-1 remain unknown. The increase in the expression of c-Myc in stimulated XBP-1-deficient B cells suggests a mechanism by which the transcription factor exerts its effects, but the authors note that XBP-1 does not directly repress the c-myc promoter. XBP-1 is not specific to B cells and plays a role in the development of other immune cell types as well as other organ tissues, most notably the liver. The effects of mosaicism in nonlymphoid tissues of chimeric mice in vivo is difficult to know. The identification of this critical factor in B cell terminal differentiation is a promising start to unraveling the mechanisms of plasma cell generation.
The RAG-2 complementation system is more fully described in this article:
Chen J, Lansford R, Stewart V, Young F, Alt FW: RAG-2-deficient blastocyst complementation: an assay of gene function in lymphocyte development
Proc Natl Acad Sci USA 1993, 90:4528-4532 (PubMed abstract).