B lymphocyte-induced maturation protein-1 (Blimp-1) maintains plasma cell survival by directly suppressing apoptosis signal-regulating kinase 1 (ASK1) (P1463)

Abstract

Terminally differentiated, antibody-secreting plasma cells are the end-stage effectors of humoral immune responses. Understanding the regulatory mechanisms that maintain the longevity of plasma cells provides a rational basis for designing strategies to enhance the levels of vaccine-induced antibodies. Blimp-1 orchestrates plasma cell differentiation by silencing the gene expression program of mature B cells. We showed that long-lived plasma cells in the bone marrow require the continuous presence of Blimp-1. Inhibition of Blimp-1 in plasma cells caused apoptosis. We performed microarray study examining the differential gene expression following depletion of Blimp-1 in plasma cells and uncovered that Blimp-1 suppresses apoptosis signal-regulating kinase 1 (ASK1). Blimp-1 directly suppresses ASK1 transcription. Knocking down ASK1 and Blimp-1 together in plasma cells blocked Blimp-1 knockdown-mediated apoptosis. Furthermore, ASK1 plays a negative role in survival of long-lived and short-lived plasma cells. ASK1 activity was induced during differentiation of short-lived plasma cells, and when produced by ASK1-deficient mice these cells survived better than those of control mice. Similarly, antigen-specific long-lived plasma cells generated by immunization accumulated in ASK1-deficient mice. Given that ASK1 induces apoptosis in response to stress, we rationalized that long-lived plasma cells may require sustained suppression of ASK1 by Blimp-1 to maintain survival.