Galectin-3 mediates IL-4-induced survival and differentiation of B cells: functional cross-talk and implications during Trypanosoma cruzi infection

J Immunol. 2004 Jan 1;172(1):493-502. doi: 10.4049/jimmunol.172.1.493.

Abstract

The role of transcription factors in B cell survival and differentiation has been delineated during the last years. However, little is known about the intermediate signals and the intracellular pathways that control these events. In this study, we provide evidence both in vitro and in vivo, showing that galectin-3 (Gal-3), a beta-galactoside-binding protein, is a critical mediator of B cell differentiation and survival. Although Gal-3 is not expressed in resting B cells from normal mice, its expression is markedly induced after activation with stimuli such as IL-4 and CD40 cross-linking. These signals promote survival and block the final differentiation of these cells, thus allowing the rising of a memory B cell phenotype. In addition, Gal-3 is expressed in B cells from Trypanosoma cruzi-infected mice, which received signals for activation and differentiation in vivo. By using an antisense strategy, we determined that Gal-3 is a critical signal mediating the effects of IL-4 on B cell fate. Blockade of intracellular Gal-3 in vitro abrogated IL-4-induced survival of activated B cells, favoring the differentiation toward a plasma cell pathway. Moreover, B cells with restrained endogenous Gal-3 expression failed to down-regulate the Blimp-1 transcription factor after IL-4 stimulation. Finally, inhibition of Gal-3 in vivo skewed the balance toward plasma cell differentiation, which resulted in increased Ig production and parasite clearance during T. cruzi infection. Thus, the present study provides evidence of a novel role for Gal-3 as an intracellular mediator of B cell survival and a checkpoint in IL-4-induced B cell commitment toward a memory phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocyte Subsets / cytology*
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocyte Subsets / metabolism
  • B-Lymphocyte Subsets / parasitology
  • Cell Communication / physiology*
  • Cell Differentiation / immunology
  • Cell Survival / immunology
  • Cells, Cultured
  • Chagas Disease / immunology*
  • Chagas Disease / metabolism
  • Galectin 3 / biosynthesis
  • Galectin 3 / physiology*
  • Immunologic Memory
  • Immunophenotyping
  • Interleukin-4 / pharmacology
  • Interleukin-4 / physiology*
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred BALB C
  • Positive Regulatory Domain I-Binding Factor 1
  • RNA, Messenger / biosynthesis
  • Repressor Proteins / biosynthesis
  • Repressor Proteins / genetics
  • Repressor Proteins / physiology
  • Signal Transduction / immunology*
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • Transcription Factors / physiology
  • Trypanosoma cruzi / immunology*
  • Up-Regulation / immunology

Substances

  • Galectin 3
  • Prdm1 protein, mouse
  • RNA, Messenger
  • Repressor Proteins
  • Transcription Factors
  • Interleukin-4
  • Positive Regulatory Domain I-Binding Factor 1