T cell leukemia/lymphoma 1 and galectin-1 regulate survival/cell death pathways in human naive and IgM+ memory B cells through altering balances in Bcl-2 family proteins

J Immunol. 2009 Feb 1;182(3):1490-9. doi: 10.4049/jimmunol.182.3.1490.

Abstract

BCR signaling plays a critical role in purging the self-reactive repertoire, or in rendering it anergic to establish self-tolerance in the periphery. Differences in self-reactivity between human naive and IgM(+) memory B cells may reflect distinct mechanisms by which BCR signaling dictates their survival and death. Here we demonstrate that BCR stimulation protected naive B cells from apoptosis with induction of prosurvival Bcl-2 family proteins, Bcl-x(L) and Mcl-1, whereas it rather accelerated apoptosis of IgM(+) memory B cells by inducing proapoptotic BH3-only protein Bim. We found that BCR-mediated PI3K activation induced the expression of Mcl-1, whereas it inhibited Bim expression in B cells. Phosphorylation of Akt, a downstream molecule of PI3K, was more sustained in naive than IgM(+) memory B cells. Abundant expression of T cell leukemia/lymphoma 1 (Tcl1), an Akt coactivator, was found in naive B cells, and enforced expression of Tcl1 induced a high level of Mcl-1 expression, resulting in prolonged B cell survival. In contrast, Galectin-1 (Gal-1) was abundantly expressed in IgM(+) memory B cells, and inhibited Akt phosphorylation, leading to Bim up-regulation. Enforced expression of Gal-1 induced accelerated apoptosis in B cells. These results suggest that a unique set of molecules, Tcl1 and Gal-1, defines distinct BCR signaling cascades, dictating survival and death of human naive and IgM(+) memory B cells.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / immunology
  • Apoptosis Regulatory Proteins / biosynthesis
  • Apoptosis Regulatory Proteins / genetics
  • B-Lymphocyte Subsets / cytology
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocyte Subsets / metabolism
  • Bcl-2-Like Protein 11
  • Cell Death / immunology
  • Cell Differentiation / immunology*
  • Cell Survival / immunology
  • Cells, Cultured
  • Galectin 1 / biosynthesis
  • Galectin 1 / genetics
  • Galectin 1 / physiology*
  • Humans
  • Immunoglobulin M / biosynthesis*
  • Immunologic Memory*
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Receptors, Antigen, B-Cell / metabolism
  • Receptors, Antigen, B-Cell / physiology
  • Resting Phase, Cell Cycle / immunology
  • Signal Transduction / immunology*
  • bcl-X Protein / biosynthesis
  • bcl-X Protein / genetics

Substances

  • Apoptosis Regulatory Proteins
  • BCL2L1 protein, human
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Galectin 1
  • Immunoglobulin M
  • Membrane Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Antigen, B-Cell
  • TCL1A protein, human
  • bcl-X Protein