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.
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.
Tabrizi
Siamak Jabbarzadeh
SJ
Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Niiro
Hiroaki
H
Masui
Mariko
M
Yoshimoto
Goichi
G
Iino
Tadafumi
T
Kikushige
Yoshikane
Y
Wakasaki
Takahiro
T
Baba
Eishi
E
Shimoda
Shinji
S
Miyamoto
Toshihiro
T
Hara
Toshiro
T
Akashi
Koichi
K
D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D016923:Cell Death / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D037483:Galectin 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007075:Immunoglobulin M / Q000096:biosynthesis*; D007156:Immunologic Memory; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism / Q000502:physiology; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D037483:Galectin 1; D007075:Immunoglobulin M; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; C090851:TCL1A protein, human; D051020:bcl-X Protein