scholarly journals X-Linked Lymphoproliferative Disease

2000 ◽  
Vol 192 (3) ◽  
pp. 337-346 ◽  
Author(s):  
Silvia Parolini ◽  
Cristina Bottino ◽  
Michela Falco ◽  
Raffaella Augugliaro ◽  
Silvia Giliani ◽  
...  
Keyword(s):  
B Cell ◽  
Nk Cells ◽  
Cell Lines ◽  
Nk Cell ◽  
Hla Class I ◽  
Lymphoproliferative Disease ◽  
Class I ◽  
Src Homology 2 ◽  
Src Homology ◽  
Src Homology 2 Domain

2B4 is a surface molecule involved in activation of the natural killer (NK) cell–mediated cytotoxicity. It binds a protein termed Src homology 2 domain–containing protein (SH2D1A) or signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which in turn has been proposed to function as a regulator of the 2B4-associated signal transduction pathway. In this study, we analyzed patients with X-linked lymphoproliferative disease (XLP), a severe inherited immunodeficiency characterized by critical mutations in the SH2D1A gene and by the inability to control Epstein-Barr virus (EBV) infections. We show that, in these patients, 2B4 not only fails to transduce triggering signals, but also mediates a sharp inhibition of the NK-mediated cytolysis. Other receptors involved in NK cell triggering, including CD16, NKp46, NKp44, and NKp30, displayed a normal functional capability. However, their activating function was inhibited upon engagement of 2B4 molecules. CD48, the natural ligand of 2B4, is highly expressed on the surface of EBV+ B cell lines. Remarkably, NK cells from XLP patients could not kill EBV+ B cell lines. This failure was found to be the consequence of inhibitory signals generated by the interaction between 2B4 and CD48, as the antibody-mediated disruption of the 2B4–CD48 interaction restored lysis of EBV+ target cells lacking human histocompatibility leukocyte antigen (HLA) class I molecules. In the case of autologous or allogeneic (HLA class I+) EBV+ lymphoblastoid cell lines, restoration of lysis was achieved only by the simultaneous disruption of 2B4–CD48 and NK receptor–HLA class I interactions. Molecular analysis revealed that 2B4 molecules isolated from either XLP or normal NK cells were identical. As expected, in XLP-NK cells, 2B4 did not associate with SH2D1A, whereas similar to 2B4 molecules isolated from normal NK cells, it did associate with Src homology 2 domain–containing phosphatase 1.

HLA Influence on NK Cell Expansion

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4924-4924
Author(s):  
Jennifer Schellekens ◽  
Anna Stserbakova ◽  
Madis Tõns ◽  
Hele Everaus ◽  
Marcel GJ Tilanus ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Lines ◽  
Cell Expansion ◽  
Nk Cell ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Haematopoietic Stem Cell ◽  
Specific Priming

Abstract Natural Killer (NK) cells are effector cells in the innate immune system. The anti-leukaemic capacities of NK cells in haematopoietic stem cell transplantation make these cells a potential treatment modality to improve clinical outcome. Immunotherapy with NK cells requires transfusion of large quantities, which obviates the need for an in vitro culture system for NK cells. The killer cell immunoglobulin-like receptors (KIR) on NK cells recognise defined groups of HLA class I alleles. To elucidate the influence of these interactions on proliferation, the peripheral blood mononuclear cells (PBMCs) of 29 patients and donors were cultured in CellGro SCGM with IL-2 and OKT3 antibody to expand the NK cell fraction. The killer cell immunoglobulin-like receptor (KIR) and HLA repertoire were determined by sequence specific priming and sequence based typing respectively. The percentage of NK cell expansion from the total PBMC fraction varied between 5.4% and 71.6%. A significantly better NK cell expansion was observed for individuals homozygous for HLA-C epitope group 2 (p<0.05). For evaluation of cytolytic competence of the cultured NK cells, specific killing of an HLA class I expression deficient LCL 721.221 cell line and three 721.221 cell lines transfected with different HLA-C alleles was determined. A significantly better NK cell-induced specific cytotoxicity was observed towards the untransfected 721.221 cells compared to the HLA-C transfected 721.221 cells. No significant differences were observed between killing of the three HLA-C transfected 721.221 cell lines. We have shown that cytolytic capacities of the cultured NK cells are maintained and in vitro expansion of NK cells is dependant on the presence of HLA-C alleles.

NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1428-1436 ◽  
Author(s):  
Stefan Diermayr ◽  
Heike Himmelreich ◽  
Bojana Durovic ◽  
Arina Mathys-Schneeberger ◽  
Uwe Siegler ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Cell Surface ◽  
Nk Cells ◽  
Cell Lines ◽  
Nk Cell ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Inhibitory Effect ◽  
Class I ◽  
The Impact

Abstract This study exploited alloreactivity of natural killer (NK) cells for augmenting the recognition of human acute myeloid leukemia (AML). To circumvent the inhibitory effect of killer immunoglobulin receptor (KIR) signaling, we generated NK-cell lines with single KIR specificities for major human leukocyte antigen (HLA) class I allotypes. We demonstrated efficient cytolysis of KIR-HLA class I–mismatched primary AML blasts even at low effector-to-target ratios. To define the impact of tumor-associated activating NKG2D-ligands (NKG2D-L), 66 AML patients at diagnosis were analyzed. NKG2D-L were selectively expressed on monoblastic cells in AML M4 and M5 yet absent or weakly expressed on myeloblastic cells in all AML subtypes. Paucity of cell-surface NKG2D-L was not the result of shedding because levels of soluble ULBP1 ligand measured in AML plasma were in the normal range. Notably, purified NKG2D-L+ monoblastic cells were more susceptible to NK-mediated killing than NKG2D-L− myeloblastic cells. Accordingly, induction of cell-surface NKG2D-L by treatment with the histone deacetylase inhibitor, valproic acid, rendered cells more sensitive to NK cytolysis. These data suggest that adoptive transfer of selected populations of alloreactive HLA class I–mismatched NK cells in combination with pharmacologic induction of NKG2D-L merits clinical evaluation as novel approaches to immunotherapy of human AML.

A Novel Mechanism of Action of Bortezomib: Proteasome Inhibition Down-Regulates HLA-Class I on Myeloma and Enhances NK Cell-Mediated Lysis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1525-1525
Author(s):  
Jumei Shi ◽  
Guido J. Tricot ◽  
Priyangi A. Malaviarachchi ◽  
Tarun K. Garg ◽  
Susann M. Szmania ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Cell Surface ◽  
Nk Cells ◽  
Cell Lines ◽  
Nk Cell ◽  
Cell Activity ◽  
Hla Class I ◽  
Class I ◽  
Target Cells ◽  
Down Regulation

Abstract Introduction: Natural killer (NK) cell activity is regulated by a dynamic balance between inhibitory and activating receptors that recognize ligands on target cells. Human leukocyte antigen (HLA)-class I, particularly HLA-C and -Bw4 molecules, are key ligands transmitting inhibitory signals to NK cells. NK cells avidly lyse tumor cells that do not display such inhibitory KIR-ligands. The proteasome is responsible for the generation of peptides that bind to and stabilize class I molecules at the cell surface. We hypothesized that bortezomib, a partial proteasome inhibitor that is clinically approved for the treatment of refractory/relapsed myeloma (MM), could reduce HLA expression on MM cells and thus enhance NK cell-mediated cytotoxicity. Methods: HLA-class I or HLA-C expression was assessed using flow cytometry, after gating on AnnexinV/PI double negative cells, and/or confocal microscopy. Expression of other proteins was measured by flow cytometry using specific mAb. NK cell-mediated lysis of myeloma cells was measured by 51Cr-release. Results: Bortezomib at clinically attainable concentrations down-regulated HLA-class I expression on MM cells in a time- and dose-dependent fashion. Reduction of class I post-10 nM bortezomib treatment was observed in all myeloma cell lines tested (n=10), by a median of 49% (range: 19–66%). A similar decrease of HLA-class I was obtained in 10–50 nM bortezomib treated primary MM cells (n=6). Bortezomib significantly enhanced the sensitivity of MM cells to allogeneic and autologous NK cell-mediated lysis. Further, the level of reduction in HLA-class I expression correlated well with increased susceptibility to lysis by NK cells. The level of down-regulation of HLA-class I induced by bortezomib was reproduced by incubating MM cells with HLA-blocking antibody and resulted in equipotent enhancement of NK cell-mediated lysis (Figure 1). The extent of HLA-class I down-regulation by bortezomib was therefore biologically relevant. Down-regulation of HLA-class I was also observed in vivo on purified MM cells 48 hours after a single dose of bortezomib, by a median of 47% (range: 16–63%, n=6, P= .002). HLA-C expression (the principal NK cell inhibitory ligand) was rescued by exogenous provision of HLA-C binding peptides providing a mechanistic explanation for the effect of bortezomib on HLA-class I expression. Finally, we did not observe bortezomib-mediated enhancement of NK cell-mediated lysis of myeloma through receptors other than the KIR receptor family, including tumor necrosis factor related apoptosis-inducing ligand, NKG2D and natural cytotoxicity receptors. HLA-class I down-regulation was not observed in renal cell and breast carcinoma cell lines, which is in keeping with the remarkable activity of bortezomib in myeloma. Our findings have clear therapeutic implications for MM and other NK cell-sensitive malignancies in the context of both allogeneic and autologous adoptively transferred NK cells. Figure 1. Reduced class I on MM cell surface results in NK cell-mediated recognition and lysis Figure 1. Reduced class I on MM cell surface results in NK cell-mediated recognition and lysis

Uptake of CCR7 and acquisition of migratory properties by human KIR+ NK cells interacting with monocyte-derived DC or EBV cell lines: regulation by KIR/HLA-class I interaction

Blood ◽  
2009 ◽  
Vol 114 (19) ◽  
pp. 4108-4116 ◽  
Author(s):  
Emanuela Marcenaro ◽  
Claudia Cantoni ◽  
Silvia Pesce ◽  
Carola Prato ◽  
Daniela Pende ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Lines ◽  
Chemokine Receptor ◽  
De Novo ◽  
Nk Cell ◽  
Hla Class I ◽  
Class I ◽  
Cell Contact ◽  
Hematopoietic Stem ◽  
Cell Clones

Abstract C-C chemokine receptor type 7 (CCR7) is a chemokine receptor playing a pivotal role in the induction of human natural killer (NK)–cell migration to lymph nodes. We show that “licensed” peripheral blood killer immunoglobulin-like receptor–positive (KIR+) NK-cell populations, as well as KIR+ NK-cell clones, de novo express CCR7 upon coculture with mature dendritic cells (mDCs) or Epstein-Barr virus (EBV)–transformed lymphoblastoid cell lines. As a consequence, they become capable of migrating in response to the CCR7-specific chemokines C-C chemokine ligand (CCL)–19 and/or CCL21. The acquisition of CCR7 by NK cells requires direct cell-to-cell contact, is detectable within a few minutes, and is due to receptor uptake from CCR7+ cells. This mechanism is tightly regulated by KIR-mediated recognition of human leukocyte antigen (HLA) class I as well as by adhesion molecules including leukocyte function-associated antigen 1 (LFA-1) and CD2. Analysis of NK-cell clones revealed that alloreactive (KIR-ligand mismatched) but not autologous NK cells acquire CCR7. These data have important implications in haploidentical hematopoietic stem cell transplantation (HSCT), in which alloreactive NK cells may acquire the ability to migrate to secondary lymphoid compartments (SLCs), where they can kill recipient antigen-presenting cells (APCs) and T cells thus preventing graft-versus-host (and host-versus-graft) reactions.

scholarly journals Src homology 2 domain–containing inositol-5-phosphatase and CCAAT enhancer-binding protein β are targeted by miR-155 in B cells of Eμ-MiR-155 transgenic mice

Blood ◽  
2009 ◽  
Vol 114 (7) ◽  
pp. 1374-1382 ◽  
Author(s):  
Stefan Costinean ◽  
Sukhinder K. Sandhu ◽  
Irene M. Pedersen ◽  
Esmerina Tili ◽  
Rossana Trotta ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
High Grade ◽  
Src Homology 2 ◽  
Enhancer Binding Protein ◽  
Src Homology ◽  
Src Homology 2 Domain

AbstractWe showed that Eμ-MiR-155 transgenic mice develop acute lymphoblastic leukemia/high-grade lymphoma. Most of these leukemias start at approximately 9 months irrespective of the mouse strain. They are preceded by a polyclonal pre–B-cell proliferation, have variable clinical presentation, are transplantable, and develop oligo/monoclonal expansion. In this study, we show that in these transgenic mice the B-cell precursors have the highest MiR-155 transgene expression and are at the origin of the leukemias. We determine that Src homology 2 domain–containing inositol-5-phosphatase (SHIP) and CCAAT enhancer-binding protein β (C/EBPβ), 2 important regulators of the interleukin-6 signaling pathway, are direct targets of MiR-155 and become gradually more down-regulated in the leukemic than in the preleukemic mice. We hypothesize that miR-155, by down-modulating Ship and C/EBPβ, initiates a chain of events that leads to the accumulation of large pre-B cells and acute lymphoblastic leukemia/high-grade lymphoma.

scholarly journals A Dual Role for Src Homology 2 Domain–Containing Inositol-5-Phosphatase (Ship) in Immunity

2000 ◽  
Vol 191 (5) ◽  
pp. 781-794 ◽  
Author(s):  
Cheryl D. Helgason ◽  
Christian P. Kalberer ◽  
Jacqueline E. Damen ◽  
Suzanne M. Chappel ◽  
Nicolas Pineault ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Development ◽  
B Cell Development ◽  
Lymphoid Development ◽  
Src Homology 2 ◽  
Src Homology ◽  
Src Homology 2 Domain ◽  
B Lymphoid

In this report, we demonstrate that the Src homology 2 domain–containing inositol-5-phosphatase (SHIP) plays a critical role in regulating both B cell development and responsiveness to antigen stimulation. SHIP−/− mice exhibit a transplantable alteration in B lymphoid development that results in reduced numbers of precursor B (fraction C) and immature B cells in the bone marrow. In vitro, purified SHIP−/− B cells exhibit enhanced proliferation in response to B cell receptor stimulation in both the presence and absence of Fcγ receptor IIB coligation. This enhancement is associated with increased phosphorylation of both mitogen-activated protein kinase and Akt, as well as with increased survival and cell cycling. SHIP−/− mice manifest elevated serum immunoglobulin (Ig) levels and an exaggerated IgG response to the T cell–independent type 2 antigen trinitrophenyl Ficoll. However, only altered B cell development was apparent upon transplantation into nonobese diabetic–severe combined immunodeficient (NOD/SCID) mice. The in vitro hyperresponsiveness, together with the in vivo findings, suggests that SHIP regulates B lymphoid development and antigen responsiveness by both intrinsic and extrinsic mechanisms.

scholarly journals Specificity of HLA class I antigen recognition by human NK clones: evidence for clonal heterogeneity, protection by self and non-self alleles, and influence of the target cell type.

1993 ◽  
Vol 178 (4) ◽  
pp. 1321-1336 ◽  
Author(s):  
V Litwin ◽  
J Gumperz ◽  
P Parham ◽  
J H Phillips ◽  
L L Lanier
Keyword(s):  
Nk Cells ◽  
Mhc Class I ◽  
Target Cell ◽  
Nk Cell ◽  
Hla Class I ◽  
Class I ◽  
Target Cells ◽  
Clonal Heterogeneity ◽  
Multiple Alleles ◽  
Wide Range

Prior studies using polyclonal populations of natural killer (NK) cells have revealed that expression of certain major histocompatibility complex (MHC) class I molecules on the membrane of normal and transformed hematopoietic target cells can prevent NK cell-mediated cytotoxicity. However, the extent of clonal heterogeneity within the NK cell population and the effect of self versus non-self MHC alleles has not been clearly established. In the present study, we have generated more than 200 independently derived human NK cell clones from four individuals of known human histocompatibility leukocyte antigens (HLA) type. NK clones were analyzed for cytolytic activity against MHC class I-deficient Epstein Barr virus (EBV) transformed B lymphoblastoid cell lines (B-LCL) stably transfected with several HLA-A, -B, or -C genes representing either self or non-self alleles. All NK clones killed the prototypic HLA-negative erythroleukemia K562 and most lysed the MHC class I-deficient C1R and 721.221 B-LCL. Analysis of the panel of HLA-A, -B, and -C transfectants supported the following general conclusions. (a) Whereas recent studies have suggested that HLA-C antigens may be preferentially recognized by NK cells, our findings indicate that 70% or more of all NK clones are able to recognize certain HLA-B alleles and many also recognize HLA-A alleles. Moreover, a single NK clone has the potential to recognize multiple alleles of HLA-A, HLA-B, and HLA-C antigens. Thus, HLA-C is not unique in conferring protection against NK lysis. (b) No simple patterns of HLA specificity emerged. Examination of a large number of NK clones from a single donor revealed overlapping, yet distinct, patterns of reactivity when a sufficiently broad panel of HLA transfectants was examined. (c) Both autologous and allogeneic HLA antigens were recognized by NK clones. There was neither evidence for deletion of NK clones reactive with self alleles nor any indication for an increased frequency of NK clones recognizing self alleles. (d) With only a few exceptions, protection conferred by transfection of HLA alleles into B-LCL was usually not absolute. Rather a continuum from essentially no protection for certain alleles (HLA-A*0201) to very striking protection for other alleles (HLA-B*5801), with a wide range of intermediate effects, was observed. (e) Whereas most NK clones retained a relatively stable HLA specificity, some NK clones demonstrated variable and heterogeneous activity over time. (f) NK cell recognition and specificity cannot be explained entirely by the presence or absence of HLA class I antigens on the target cell.(ABSTRACT TRUNCATED AT 400 WORDS)

Anti-Leukemia Activity of Alloreactive NK Cells in Haploidentical HSCT in Pediatric Patients: Re-Defining the Role of Activating and Inhibitory KIR

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3002-3002 ◽  
Author(s):  
Daniela Pende ◽  
Stefania Marcenaro ◽  
Michela Falco ◽  
Stefania Martini ◽  
Maria Ester Bernardo ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Nk Cell ◽  
Cell Subset ◽  
Hla Class I ◽  
Class I ◽  
Leukemia Cells ◽  
Hla Alleles ◽  
Time Points ◽  
Selection Of

Abstract T-cell depleted hematopoietic stem cell transplantation from haploidentical donors (haplo-HSCT) has been reported to benefit from the graft-versus-leukemia effect mediated by natural killer (NK) cells when donor displays NK alloreactivity versus the recipient. NK alloreactivity is mediated by NK receptors, namely Killer Ig-like receptors (KIR) which are specific for allotypic determinants that are shared by different HLA-class I alleles (referred to as KIR ligands). It is known that KIR2DL1 recognizes HLA-C alleles characterized by Lys at position 80 (C2 group), KIR2DL2/3 recognize HLA-C alleles characterized by Asn at position 80 (C1 group), KIR3DL1 recognizes HLA-B alleles sharing the Bw4 supertypic specificity (Bw4 group) and KIR3DL2 recognizes HLA-A3 and –A11 alleles. KIR2D/3DL are inhibitory receptors that, upon engagement with the cognate ligand, inhibit lysis. Activating KIRs, highly homologous in the extracellular domain to the inhibitory counterparts, are KIR2DS1, KIR2DS2 and KIR3DS1, but only KIR2DS1 has been shown to specifically recognize C2 group of alleles expressed on B-EBV cells. We analyzed 21 children with leukemia receiving haplo-HSCT from a relative after a myeloablative conditioning regimen; in all pairs, the expression of a given KIR ligand (HLA class I allele) of the donor was missing in the patient (i.e. KIR ligand-mismatched haplo-HSCT). T-cell depletion was performed through positive selection of CD34+ cells; no pharmacological immune suppression was employed after HSCT. KIR genotype of all donors was evaluated to detect the presence of the various inhibitory and activating KIR genes. Phenotypic analyses were performed on NK cells derived from the donor and the patient at different time points after HSCT. Thanks to the availability of new mAbs able to discriminate between the inhibitory and the activating forms of a certain KIR, we could identify the alloreactive NK cell subset at the population level. These alloreactive NK cells express the KIR specific for the KIR ligand-mismatch (permissive inhibitory KIR) and the activating KIR (if present), while they do not express all inhibitory KIR specific for the patient HLA alleles and NKG2A. Thus, in most instances, we could precisely identify the size of the alloreactive NK cell subset in the donor and in the reconstituted repertoire of the recipient. Functional assays were performed to assess alloreactivity, using appropriate B-EBV cell lines and, if available, patient’s leukemia blasts. In some cases, also NK cell clones were extensively studied, for phenotype and receptor involvement in killing activity. We found that, in most transplanted patients, variable proportions of donor-derived alloreactive NK cells displaying anti-leukemia activity were generated and maintained even at late time-points after transplantation. Donor-derived KIR2DL1+ NK cells isolated from the recipient displayed the expected capability of selectively killing C1/C1 target cells, including patient leukemia blasts. Differently, KIR2DL2/3+ NK cells displayed poor alloreactivity against leukemia cells carrying HLA alleles belonging to the C2 specificity. Unexpectedly, this was due to recognition of C2 by KIR2DL2/3, as revealed by receptor blocking experiments and by binding assays of soluble KIR to HLA-C transfectants. Remarkably, however, C2/C2 leukemia blasts were killed by KIR2DL2/3+ (or by NKG2A+) NK cells that co-expressed KIR2DS1. This could be explained by the ability of KIR2DS1 to directly recognize C2 on leukemia cells. A role for the KIR2DS2 activating receptor in leukemia cell lysis could not be established. Taken together, these findings provide new information on NK alloreactivity in haplo-HSCT that may greatly impact on the selection of the optimal donor.

Analyses of HLA-C–specific KIR repertoires in donors with group A and B haplotypes suggest a ligand-instructed model of NK cell receptor acquisition

Blood ◽  
2011 ◽  
Vol 117 (1) ◽  
pp. 98-107 ◽  
Author(s):  
Kathrin Schönberg ◽  
Martina Sribar ◽  
Jürgen Enczmann ◽  
Johannes C. Fischer ◽  
Markus Uhrberg
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Hla Class I ◽  
Cell Receptor ◽  
Suppressive Effect ◽  
Class I ◽  
Nk Cell Differentiation ◽  
Group A ◽  
Common Group ◽  
Group B

Abstract To determine the influence of KIR and HLA class I polymorphism on human NK cell repertoires, 32 different clonotypes representing all possible combinations of 4 inhibitory KIR and NKG2A were analyzed by multicolor flow cytometry. In donors homozygous for the common group A KIR haplotype, a significant influence of HLA-C ligands was seen: KIR repertoires were dominated by clonotypes expressing a single KIR for the respective cognate ligand, either the C1-specific KIR2DL3 or C2-specific KIR2DL1. In contrast, in donors possessing the polymorphic group B haplotypes, a similar adaptation to cognate HLA-C was lacking. We suggest that this discrepancy is largely the result of a suppressive effect of the group B–specific KIR2DL2 on the frequency of KIR2DL1+ NK cells. In functional assays, KIR2DL2 not only recognized C1 but also C2 ligands, showing overlapping specificity with KIR2DL1. Moreover, using an NK cell differentiation assay we show sequential acquisition of KIR2DL2 before KIR2DL1 on developing NK cells. Together, these observations are compatible with a ligand-instructed model of NK cell education, in which recognition of HLA class I by an inhibitory receptor (KIR2DL2) suppresses subsequent expression of a second receptor (KIR2DL1) of related specificity. Importantly, the ligand-instructed model fits to the observed KIR repertoires in both broad KIR haplotype groups.

scholarly journals Differential Regulation of B Cell Development, Activation, and Death by the Src Homology 2 Domain–Containing 5′ Inositol Phosphatase (Ship)

2000 ◽  
Vol 191 (9) ◽  
pp. 1545-1554 ◽  
Author(s):  
Anne Brauweiler ◽  
Idan Tamir ◽  
Joseph Dal Porto ◽  
Robert J. Benschop ◽  
Cheryl D. Helgason ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Cell Development ◽  
B Cell Development ◽  
Inositol Phosphatase ◽  
Src Homology 2 ◽  
Src Homology ◽  
Src Homology 2 Domain ◽  
Deficient Mice

Although the Src homology 2 domain–containing 5′ inositol phosphatase (SHIP) is a well-known mediator of inhibitory signals after B cell antigen receptor (BCR) coaggregation with the low affinity Fc receptor, it is not known whether SHIP functions to inhibit signals after stimulation through the BCR alone. Here, we show using gene-ablated mice that SHIP is a crucial regulator of BCR-mediated signaling, B cell activation, and B cell development. We demonstrate a critical role for SHIP in termination of phosphatidylinositol 3,4,5-triphosphate (PI[3,4,5]P3) signals that follow BCR aggregation. Consistent with enhanced PI(3,4,5)P3 signaling, we find that splenic B cells from SHIP-deficient mice display enhanced sensitivity to BCR-mediated induction of the activation markers CD86 and CD69. We further demonstrate that SHIP regulates the rate of B cell development in the bone marrow and spleen, as B cell precursors from SHIP-deficient mice progress more rapidly through the immature and transitional developmental stages. Finally, we observe that SHIP-deficient B cells have increased resistance to BCR-mediated cell death. These results demonstrate a central role for SHIP in regulation of BCR signaling and B cell biology, from signal driven development in the bone marrow and spleen, to activation and death in the periphery.

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