Vav proteins regulate peripheral B-cell survival

Abstract

IntroductionSignal transduction pathways initiated by the B-cell antigen receptor and the related pre-B-cell receptor regulate the developmental progress, survival, and activation of B cells. 1 During B-cell development in the bone marrow, successful immunoglobulin heavy (IgH) chain rearrangement leads to the assembly of a functional pre-B-cell receptor (pre-BCR) that additionally contains the V-pre-B and 5 proteins. This receptor signals both cellular proliferation and allelic exclusion of further IgH rearrangement. Subsequent productive rearrangement of or light chain, and successful pairing with heavy chain, lead to the expression of membrane IgM and define the immature B cell. B-cell development beyond the immature B-cell stage is crucially dependent on BCR signaling. Immature B cells are negatively selected after encounter with self-antigen but also require IgM-mediated signal transduction to undergo maturation into long-lived recirculating B cells. [2][3][4] This process, which has been termed positive selection, gives rise to follicular entry and increased longevity of mature B cells. The mechanisms that mediate B-cell-positive selection remain unclear. It is established that expression of the BCR is required to protect mature B cells from apoptosis. 5,6 Furthermore, immunoreceptor tyrosine-based activation motif (ITAM)-deficient mutants of CD79a, which allow BCR assembly and expression, reveal an essential role for this BCR-associated signal transducer in the generation of the survival signal. 6 Moreover, B cells deficient in the spleen tyrosine kinase (Syk) are unable to undergo positive selection. 7 In addition, the mutation of other components of the BCR signal transduction apparatus display defects in positive selection, though these are less severe than those reported for Syk mutants. 8 Competition between newly formed and mature recirculating B cells for limiting resources 9 plays an important role in controlling entry into the mature pool and may be regulated by interactions between B cells and stromal cells.In mouse splenic B cells and in B-cell lines, members of the nuclear factor-kappaB (NF-B) family of transcription factors are constitutively active and located in the nucleus. This contrasts with most cell types in which NF-B is found as an inactive complex in the cytoplasm. 10 Gene-targeting experiments have demonstrated roles for NF-B family members in the regulation of B-cell survival and activation. 11 Splenic B cells constitutively express nuclear NF-B primarily in the form of p50/cellular reticuloendotheliosis (c-Rel) and p52/RelB complexes. P52 is generated by the so-called alternative pathway of NF-B activation that is regulated by the survival cytokine B-cell activation factor (BAFF). 12,13 Maintenance of p50/c-Rel activity is mediated through a novel Ca 2ϩ -dependent, but proteasome-and ubiquitin ligase-independent, degradation of the inhibitor protein IB. [14][15][16] This novel pathway is still only partly understood, but it demonstrates a requirement for calmodulin and not calcine...

The CD49d/CD29 complex is physically and functionally associated with CD38 in B-cell chronic lymphocytic leukemia cells

“…5,11,47 In the present study, a more marked anti-apoptotic effect was exerted upon CD49d/VCAM-1 interactions in CD49d þ CD38 þ cells, as compared with CD49d þ CD38 À cells. This observation can be explained by a more efficient adhesion of CD49d þ CD38 þ cells, and a consequent more pronounced activation of the anti-apoptotic machinery, 5,11 also thanks to the contribution to the survival process of specific signaling proteins, including Vav-1, 48 already recruited to the adhesion site. Although further studies are needed to fully disclose the mechanism(s) behind the role of CD38 in CD49d-mediated adhesion in CLL, the present work provides evidence of a functional interaction between these molecules, which could explain at least in part the negative clinical outcome characterizing patients with a CD49d þ CD38 þ CLL clone.…”

ATM, CTLA4, MNDA, andHEM1in High versus Low CD38–Expressing B-Cell Chronic Lymphocytic Leukemia

“…BCL2 has been regarded as the main culprit in CLL (41) and this is the first report demonstrating direct correlation between BCL2 levels and CD38 expression levels. Similarly, expression of other genes, such as NFATC2 and VAV3, that are involved in B-cell differentiation and survival, respectively (42,43), directly correlated with CD38 expression. VAV3 up-regulates BCL2 via nuclear factor-nB and thus shows that higher VAV3 expression in CD38 high expressing CLL cells may lead to higher survival in these cells (44).…”

Natural killer cells play a key role in the antitumor immunity generated by chaperone‐rich cell lysate vaccination

“…26,27 However, less is known about its role in NK cells. To our knowledge, there are no published data examining the role of NF-jB in HSP-induced NK cell activation.…”