Article

The Follicular versus Marginal Zone B Lymphocyte Cell Fate Decision Is Regulated by Aiolos, Btk, and CD21

Cancer Center and, Massachusetts General Hospital and, Harvard Medical School, Boston, MA 02129, USA.
Immunity (Impact Factor: 19.75). 06/2001; 14(5):603-15. DOI: 10.1016/S1074-7613(01)00135-2
Source: PubMed

ABSTRACT Most splenic B cells in mice that lack Aiolos are mature IgD(hi)IgM(lo) follicular lymphocytes, suggesting that maturation signals delivered via the BCR are enhanced in the absence of Aiolos. The enhanced maturation of follicular B cells is accompanied by the absence of MZ B lymphocytes and the downregulation of CD21 expression in follicular B cells, all of which depend on the generation of signals via Btk, which is in epistasis to Aiolos. The inverse relationship between the strength of BCR signaling and MZ B cell development is supported by an examination of MZ B cells in CD21 null mice. These data support the view that antigens (in contrast to "tonic" signals) drive the development of naive B cells.

Download full-text

Full-text

Available from: Katia Georgopoulos, Aug 06, 2014
0 Followers
 · 
84 Views
 · 
25 Downloads
  • Source
    • "The T2 transitional B cell is thought to be the common precursor for both MZ B and follicular B-2 B cells [4]. Studies on gene-targeted mice have allowed the identification of several MZB cell determinants [5], [6], [7], [8], [9], [10], including effectors of Notch [11], [12], [13], [14], [15], [16], [17] and BCR [18], [19], although their contribution to MZB cell establishment/maintenance remains poorly understood [3], [20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Eps15 is an endocytic adaptor protein involved in clathrin and non-clathrin mediated endocytosis. In Caenorhabditis elegans and Drosophila melanogaster lack of Eps15 leads to defects in synaptic vesicle recycling and synapse formation. We generated Eps15-KO mice to investigate its function in mammals. Eps15-KO mice are born at the expected Mendelian ratio and are fertile. Using a large-scale phenotype screen covering more than 300 parameters correlated to human disease, we found that Eps15-KO mice did not show any sign of disease or neural deficits. Instead, altered blood parameters pointed to an immunological defect. By competitive bone marrow transplantation we demonstrated that Eps15-KO hematopoietic precursor cells were more efficient than the WT counterparts in repopulating B220(+) bone marrow cells, CD19(-) thymocytes and splenic marginal zone (MZ) B cells. Eps15-KO mice showed a 2-fold increase in MZ B cell numbers when compared with controls. Using reverse bone marrow transplantation, we found that Eps15 regulates MZ B cell numbers in a cell autonomous manner. FACS analysis showed that although MZ B cells were increased in Eps15-KO mice, transitional and pre-MZ B cell numbers were unaffected. The increase in MZ B cell numbers in Eps15 KO mice was not dependent on altered BCR signaling or Notch activity. In conclusion, in mammals, the endocytic adaptor protein Eps15 is a regulator of B-cell lymphopoiesis.
    PLoS ONE 11/2012; 7(11):e50818. DOI:10.1371/journal.pone.0050818 · 3.23 Impact Factor
  • Source
    • "It has been well documented that weak BCR signaling leads B cells to develop into MZ B cells. For example, mutations of molecules that attenuate BCR signaling, such as Aiolos or CD22, result in an increased number of FO B cells, while MZ B cells are absent [25], [26]. Conversely, deficiencies in molecules that reduce BCR signaling, such as CD21/CR2 deficiency, increase the number of MZ B cells [25]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Both the B cell antigen receptor (BCR) signaling and Notch signaling pathway play important roles in marginal zone (MZ) B cell development; however, if and how these two signaling pathways engage in crosstalk with each other remain unclear. In the present study, IgH transgenic mice (TgV(H)3B4) were crossed with mice with Notch downstream transcription factor RBP-J floxed alleles (RBP-J(f/f)) and Mx-Cre transgene. Subsequently, MZ B cell development was analyzed in 3B4/Cre/RBP-J(f/f) mice that expressed the transgenic 3B4 IgH and exhibited a deficiency in Notch signaling in B cells upon poly (I:C) injection. We observed that MZ B cell numbers were severely reduced, but still detectable in 3B4/Cre/RBP-J(f/f) mice, in contrast to increased numbers of MZ B cells in TgV(H)3B4 mice and almost no MZ B cells in Cre/RBP-J(f/f) mice. The majority of the MZ B cells in the 3B4/Cre/RBP-J(f/f) mice had the same antigen specificity with that of 3B4 antibody, indicating that a particular BCR specificity might direct MZ B cell development in the absence of Notch signaling. The number of MZ B precursor (MZP) cells was reduced sharply in 3B4/Cre/RBP-J(f/f) mice, and the number of transitional stage 1 and transitional stage 2 cells did not change that much, indicating that the interaction between BCR and Notch signaling likely occurred during the T2-MZP stage. Based on the transgenic mouse model, our data indicate that MZ B cells with certain BCR specificity can develop in a Notch-RBP-J independent manner.
    PLoS ONE 06/2012; 7(6):e38894. DOI:10.1371/journal.pone.0038894 · 3.23 Impact Factor
  • Source
    • "Strong BCR signaling preferentially commits developing B cells to the FO B cell fate, whereas weak BCR signaling favours the MZ B cell fate [2], [6]. For example, mice deficient in CD22, a negative regulator of BCR signaling, have a reduced number of MZ B cells [45], whereas Aiolos deficient mice have enhanced BCR signaling, and a concomitant reduction in the number of splenic MZ B cells with increased numbers of FO B cells [46], [47]. The Aiolos phenotype can be suppressed by intercrossing the Aiolos-deficient mice with Xid mice, which lack a fully functional BTK tyrosine kinase. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The homeodomain-interacting protein kinase (HIPK) family is comprised of four highly related serine/threonine kinases originally identified as co-repressors for various homeodomain-containing transcription factors. The HIPKs have been shown to be involved in growth regulation and apoptosis, with numerous studies highlighting HIPK regulation of the tumor suppressor p53. In this study, we have discovered a B cell homeostatic defect in HIPK1-deficient (HIPK1(-/-)) mice. Lymphopoietic populations within the thymus and bone marrow of HIPK1(-/-) mice appeared normal based upon FACS analysis; however, the spleen exhibited a reduced number of total B cells with a significant loss of transitional-1 and follicular B cell populations. Interestingly, the marginal zone B cell population was expanded in HIPK1(-/-) mice, yielding an increased frequency of these cells. HIPK1(-/-) B cells exhibited impaired cell division in response to B cell receptor cross-linking in vitro based upon thymidine incorporation or CFSE dilution; however, the addition of CD40L rescued HIPK1(-/-) proliferation to wild-type levels. Despite the expanded MZ B cell population in the HIPK1(-/-) mice, the T-independent type 2 humoral response was impaired. These data identify HIPK1 as a novel kinase required for optimal B cell function in mice.
    PLoS ONE 04/2012; 7(4):e35533. DOI:10.1371/journal.pone.0035533 · 3.23 Impact Factor
Show more