1. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
2. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
3. Howard Hughes Medical Institute, Children's Hospital, Boston, Massachusetts 02115, USA
4. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA
5. Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA
6. These authors contributed equally to this work.
7. Present address: Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Texas 75390, USA.

Correspondence to: Laurie H. Glimcher^1,3 Correspondence and requests for materials should be addressed to L.H.G. (e-mail: Email: lglimche@hsph.harvard.edu).

Abstract

Considerable progress has been made in identifying the transcription factors involved in the early specification of the B-lymphocyte lineage. However, little is known about factors that control the transition of mature activated B cells to antibody-secreting plasma cells. Here we report that the transcription factor XBP-1 is required for the generation of plasma cells. XBP-1 transcripts were rapidly upregulated in vitro by stimuli that induce plasma-cell differentiation, and were found at high levels in plasma cells from rheumatoid synovium. When introduced into B-lineage cells, XBP-1 initiated plasma-cell differentiation. Mouse lymphoid chimaeras deficient in XBP-1 possessed normal numbers of activated B lymphocytes that proliferated, secreted cytokines and formed normal germinal centres. However, they secreted very little immunoglobulin of any isotype and failed to control infection with the B-cell-dependent polyoma virus, because plasma cells were markedly absent. XBP-1 is the only transcription factor known to be selectively and specifically required for the terminal differentiation of B lymphocytes to plasma cells.