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Klhl6 Deficiency Impairs Transitional B Cell Survival and Differentiation.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2017 Oct 01; Vol. 199 (7), pp. 2408-2420. Date of Electronic Publication: 2017 Aug 14. - Publication Year :
- 2017
-
Abstract
- Klhl6 belongs to the KLHL gene family, which is composed of an N-terminal BTB-POZ domain and four to six Kelch motifs in tandem. Several of these proteins function as adaptors of the Cullin3 E3 ubiquitin ligase complex. In this article, we report that Klhl6 deficiency induces, as previously described, a 2-fold reduction in mature B cells. However, we find that this deficit is centered on the inability of transitional type 1 B cells to survive and to progress toward the transitional type 2 B cell stage, whereas cells that have passed this step generate normal germinal centers (GCs) upon a T-dependent immune challenge. Klhl6-deficient type 1 B cells showed a 2-fold overexpression of genes linked with cell proliferation, including most targets of the anaphase-promoting complex/cyclosome complex, a set of genes whose expression is precisely downmodulated upon culture of splenic transitional B cells in the presence of BAFF. These results thus suggest a delay in the differentiation process of Klhl6-deficient B cells between the immature and transitional stage. We further show, in the BL2 Burkitt's lymphoma cell line, that KLHL6 interacts with Cullin3, but also that it binds to HBXIP/Lamtor5, a protein involved in cell-cycle regulation and cytokinesis. Finally, we report that KLHL6, which is recurrently mutated in B cell lymphomas, is an off-target of the normal somatic hypermutation process taking place in GC B cells in both mice and humans, thus leaving open whether, despite the lack of impact of Klhl6 deficiency on GC B cell expansion, mutants could contribute to the oncogenic process.<br /> (Copyright © 2017 by The American Association of Immunologists, Inc.)
- Subjects :
- Animals
B-Lymphocytes immunology
Burkitt Lymphoma pathology
Carrier Proteins genetics
Cell Differentiation
Cell Line
Cell Proliferation
Germinal Center immunology
Humans
Lymphoma, B-Cell genetics
Lymphoma, B-Cell pathology
Mice
Mutation
Precursor Cells, B-Lymphoid physiology
B-Lymphocytes physiology
Carrier Proteins physiology
Germinal Center cytology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 199
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 28807996
- Full Text :
- https://doi.org/10.4049/jimmunol.1700708