Plasma cell differentiation requires the transcription factor XBP-1

Reimold, Andreas M.
Iwakoshi, Neal N.
Manis, John
Vallabhajosyula, Prashanth
Szomolanyi-Tsuda, Eva
Gravallese, Ellen M.
Friend, Daniel
Grusby, Michael J.
Alt, Frederick
Glimcher, Laurie H.

* Department of Immunology and Infectious Diseases, Harvard School of Public Health; ‡ Department of Medicine, Harvard Medical School; ∥ Howard Hughes Medical Institute, Children's Hospital; and # Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA
❡ Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA

† These authors contributed equally to this work.

§ Present address: Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Texas 75390, USA.

Received 29 March; accepted 24 May 2001.

Correspondence and requests for materials should be addressed to L.H.G.

(e-mail: [email protected]).

Nature 412(6844):p 300-307, July 19, 2001.

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.