Do B Cells Take Advantage of 'Missing Self� Recognition?

2002 ◽  
pp. 245-264 ◽  
Author(s):  
D. Nemazee ◽  
A. Gavin
Keyword(s):  
B Cells ◽  
Self Recognition ◽  
Missing Self

Rituximab-Mediated ADCC Is Augmented by Concomitant Interference with Inhibitory Self-Recognition by Human NK Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2456-2456
Author(s):  
Liat Binyamin ◽  
R. Katherine Alpaugh ◽  
Kerry S. Campbell ◽  
Hossein Borghaei ◽  
Louis M. Weiner
Keyword(s):  
B Cells ◽  
Nk Cells ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Tumor Cell Death ◽  
Peripheral Blood Mononuclear ◽  
Self Recognition ◽  
Missing Self ◽  
Anti Cd20

Abstract The anti-CD20 monoclonal antibody, rituximab is widely used in the treatment of non-Hodgkin lymphomas. However, clinical responses to rituximab are variable. It has been demonstrated that rituximab can lead to tumor cell death by engaging the cellular immune system through antibody dependent cellular cytotoxicity (ADCC). NK cells have been shown to play a critical rule in eliminating rituximab coated B-cells, and the efficiency of killing depends on the interaction between the Fc portion of rituximab and the FcγRIII (CD16) activating receptor on NK cells. NK cell function is regulated by a complex balance of inhibitory and activating signals that enable the cells to survey their surrounding and selectively target and kill targets that do not display a “self” ligand (the “missing self hypothesis”). We hypothesized that interference with inhibitory self-recognition would augment rituximab-induced NK cell-mediated ADCC. Initial studies with the 721.221 B51 (HLA Bw4+) CD20+ cell line and NK92.26.5 cells transduced with human CD16 suggested that interference with KIR3DL1 recognition of Bw4 augmented tumor lysis in the presence of rituximab. To further test this hypothesis we employed human NK cells and autologous EBV transformed B cells from normal volunteers, and blocked the KIR3DL1 inhibitory receptor on NK cells using (Fab′)2 fragments of the DX9 antibody, in conjunction with rituximab exposure. Inhibitory blockade promoted rituximab-mediated cytotoxicity by peripheral blood mononuclear cells in three separate HLABw4+, KIR3DL1+ volunteers. These results suggest that manipulating the balance between inhibitory and activating receptors on NK cells might be applied to improve ADCC and ultimately lead to an improvement in response rates to rituximab and related lymphoma-directed antibodies that mediate ADCC. Supported by R01CA50633.

scholarly journals Immune selection during tumor checkpoint inhibition therapy paves way for NK-cell “missing self” recognition

2017 ◽  
Vol 69 (8-9) ◽  
pp. 547-556 ◽  
Author(s):  
Karl-Johan Malmberg ◽  
Ebba Sohlberg ◽  
Jodie P. Goodridge ◽  
Hans-Gustaf Ljunggren
Keyword(s):  
Nk Cell ◽  
Checkpoint Inhibition ◽  
Immune Selection ◽  
Self Recognition ◽  
Missing Self

scholarly journals Structure of Natural Killer Cell Receptor KLRG1 Bound to E-Cadherin Reveals Basis for MHC-Independent Missing Self Recognition

Immunity ◽  
2009 ◽  
Vol 31 (1) ◽  
pp. 35-46 ◽  
Author(s):  
Yili Li ◽  
Maike Hofmann ◽  
Qian Wang ◽  
Leslie Teng ◽  
Lukasz K. Chlewicki ◽  
...  
Keyword(s):  
Natural Killer Cell ◽  
Natural Killer ◽  
Killer Cell ◽  
Cell Receptor ◽  
Natural Killer Cell Receptor ◽  
Self Recognition ◽  
Missing Self ◽  
E Cadherin

scholarly journals Rosette formation between murine lymphocytes and erythrocytes. A new locus in the H-2 region.

1979 ◽  
Vol 149 (6) ◽  
pp. 1349-1359 ◽  
Author(s):  
D Primi ◽  
G K Lewis ◽  
R Triglia ◽  
J W Goodman
Keyword(s):  
T Cells ◽  
B Cells ◽  
Rosette Formation ◽  
Chromosome 17 ◽  
Splenic Lymphocytes ◽  
Recombinant Strains ◽  
Surface Immunoglobulin ◽  
Self Recognition

More than 5% of murine splenic lymphocytes form rosettes with syngeneic erythrocytes. This property was maximally expressed when the lymphocytes were cultured for 24 h before rosetting. About 70% of the rosetting lymphocytes were B cells and 30% were T cells on the basis of surface immunoglobulin and the Thy-1-antigen. Capping surface immunoglobulin had no effect on the capacity of lymphocytes to form rosettes, indicating that the receptor in question was not immunoglobulin. The capacity of lymphocytes to form rosettes with erythrocytes from other strains of mice was H-2 restricted. Extensive pairings of congenic and recombinant strains as donors of lymphocytes and erythrocytes showed that none of the known loci within the H-2 region-controlled rosetting. The involvement of regions on chromosome 17, telomeric or centromeric to H-2, was also excluded. The data were only compatible with the conclusion that this form of self-recognition is associated with a new locus (or loci) mapping between H-2G and H-2D.

scholarly journals Impact of Kindlin-3 in NK Cell-Mediated Anti-Tumor Cytotoxicity and Inflammatory Cytokine Production

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 208-208
Author(s):  
Nathan J. Schloemer ◽  
Alex M Abel ◽  
Monica S Thakar ◽  
Yan-Qing Ma ◽  
Subramaniam Malarkannan
Keyword(s):  
Nk Cells ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Nk Cell ◽  
Mhc I ◽  
Inflammatory Cytokine Production ◽  
Effector Functions ◽  
Self Recognition ◽  
Tumor Cytotoxicity ◽  
Missing Self

Abstract Natural Killer (NK) cells are innate lymphocytes that play a central role in anti-viral and anti-tumor responses through direct cytotoxicity and production of inflammatory cytokines. Tumors can evade T-cell mediated immune-surveillance by down-regulation of the Class I Major Histocompatibility Complex (MHC-I) (Haworth et al, Ped Blood and Cancer, 2015). However, this lack of 'self' MHC-I serves as an activation stimulus for NK cells to recognize tumor cells. The molecular mechanism for 'self' recognition and destruction of 'missing self' are poorly understood. Integrins facilitate cell-to-cell interactions and are hypothesized to play a role in the 'self' versus 'missing self' recognition (Crozat et al, Blood, 2011). One of the critical regulators of integrin activation is Kindlin-3, which helps in their 'inside-out' signaling. Kindlin-3 binds to the cytoplasmic tail of β2-integrin and induces a conformational change increasing ligand affinity (Ye et al, Curr Biol, 2013). Consequently, Kindlin-3 is localized at the immunologic synapse and has been shown to interact with Adhesion and Degranulation Adaptor Protein (ADAP) (Kasirer-Friede et al, Blood 2014). As our group has shown, ADAP plays a central role in the signaling transduction for inflammatory cytokine production in NK cells (Rajasekaran et al, Nat Immunol, 2013). Clinically, defects in Kindlin-3 functions in humans are manifested by severe immune deficiency and bleeding disorder defined as Leukocyte Adhesion Deficiency-III (LAD-III). Based on these observations, we hypothesized Kindlin-3-dependent integrin function is critical for NK cell-mediated anti-tumor cytotoxicity and production of inflammatory cytokines. To define the role of Kindlin-3 in NK cell effector functions, we utilized a murine model. Kindlin-3 knock-in (K3KI) mice carry a double substitution mutation disrupting the binding of Kindlin-3 to β2-integrin (Xu et al, Arterioscler Thromb Vac Biol, 2014). NK cells from K3KI mice were evaluated for development and effector functions. Flow cytometry was utilized to identify maturation and developmental populations. Inflammatory cytokine production was assessed by Interferon-γ release following NK cell and tumor co-culture as well as plate-bound antibody activation. Cytotoxicity was assessed by 51Cr-release assay and the following tumor cells were used: cells representing, 1) 'self' (RMA and EL4 thymomas with autologous MHC-I); 2) 'missing-self' (RMA/S with decreased MHC expression relative to RMA); 3) 'induced self' (EL4 thymomas stably expressing H60, an activating ligand for NKG2D; 4) 'non-self' (YAC1 lymphoma with allogeneic MHC). Our results show an overall increase in the peripheral NK populations collected from spleens of K3KI mice, as seen in patients with LAD-III. However, no significant maturational defects were noted in the bone marrow of the K3KI mice. In vitro analyses reveal that K3KI NK cells have significantly impaired anti-tumor cytotoxicity relative to wild type controls (Figure 1). There was a significant reduction in the cytotoxic ability of K3KI NK cells towards 'induced self' or 'missing self' recognition (p<0.05). In contrast, K3KI NK cells have augmented inflammatory interferon-γ cytokine production compared to wild type controls when co cultured with the same tumor models in which cytotoxicity was significantly impaired (Figure 2). These data reveal the essential role of Kindlin-3 interaction with integrin for the effector functions of the NK cell. Currently, we are delineating the signaling mechanisms which mediate this divergence in NK cell functions dependent on Kindlin-3. Our studies reveal an undefined role for Kindlin-3 in NK cells and may help to identify novel therapeutic targets to modulate NK cell effector functions. Disclosures No relevant conflicts of interest to declare.

scholarly journals Genetic and antibody-mediated reprogramming of natural killer cell missing-self recognition in vivo

2009 ◽  
Vol 106 (31) ◽  
pp. 12879-12884 ◽  
Author(s):  
C. Sola ◽  
P. Andre ◽  
C. Lemmers ◽  
N. Fuseri ◽  
C. Bonnafous ◽  
...  
Keyword(s):  
Natural Killer Cell ◽  
Natural Killer ◽  
Killer Cell ◽  
Self Recognition ◽  
Missing Self

scholarly journals Missing self-recognition of Ocil/Clr-b by inhibitory NKR-P1 natural killer cell receptors

2004 ◽  
Vol 101 (10) ◽  
pp. 3527-3532 ◽  
Author(s):  
J. R. Carlyle ◽  
A. M. Jamieson ◽  
S. Gasser ◽  
C. S. Clingan ◽  
H. Arase ◽  
...  
Keyword(s):  
Natural Killer Cell ◽  
Natural Killer ◽  
Killer Cell ◽  
Cell Receptors ◽  
Natural Killer Cell Receptors ◽  
Self Recognition ◽  
Missing Self
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