TACI deficiency impairs sustained Blimp-1 expression in B cells decreasing long-lived plasma cells in the bone marrow

Blood. 2011 Nov 24;118(22):5832-9. doi: 10.1182/blood-2011-05-353961. Epub 2011 Oct 7.

Abstract

Deficiencies in transmembrane activator and CAML interactor (TACI) result in common variable immune deficiency, a syndrome marked by recurrent infections with encapsulated microorganisms, impaired production of antibodies, and lymphoproliferation. How TACI promotes antibody production and inhibits lymphoproliferation is not understood. To answer this question, we studied the generation of immunity to protein antigens in both TACI-deficient and TACI-proficient mice. We show that TACI promotes sustained Blimp-1 expression by B cells responding to antigen, which in turn limits B-cell clonal expansion and facilitates differentiation of long-lived antibody-secreting cells. Short-term IgG secretion occurs independently of TACI as DNA double-strand breaks associated with isotype class switching induce Blimp-1 transiently, independently of TACI. Our results showing that TACI induces and maintains Blimp-1 provide, for the first time, a unified molecular and cellular mechanism explaining the primary features of common variable immune deficiency, exquisite vulnerability to infection with encapsulated organisms, lymphoproliferation, and hypogammaglobulinemia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibody Formation / genetics
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • B-Lymphocytes / physiology
  • Bone Marrow / metabolism
  • Bone Marrow / physiology
  • Bone Marrow Cells / cytology*
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / physiology
  • Cell Count
  • Cell Proliferation
  • Cells, Cultured
  • Cellular Senescence / genetics
  • Cellular Senescence / physiology
  • Down-Regulation / genetics
  • Gene Expression
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Plasma Cells / cytology*
  • Plasma Cells / metabolism
  • Positive Regulatory Domain I-Binding Factor 1
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transmembrane Activator and CAML Interactor Protein / genetics*
  • Transmembrane Activator and CAML Interactor Protein / physiology

Substances

  • Prdm1 protein, mouse
  • Tnfrsf13b protein, mouse
  • Transcription Factors
  • Transmembrane Activator and CAML Interactor Protein
  • Positive Regulatory Domain I-Binding Factor 1