Journal
JOURNAL OF IMMUNOLOGY
Volume 182, Issue 3, Pages 1490-1499Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.182.3.1490
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- Ministry of Education, Culture, Sports, Science, and Technology in Japan
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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 (Tell), an Akt coactivator, was found in naive B cells, and enforced expression of Tell 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, Tell and Gal-1, defines distinct BCR signaling cascades, dictating survival and death of human naive and IgM(+) memory B cells. The Journal of Immunology, 2009, 182: 1490-1499.
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