scholarly journals Specific and high-affinity binding of tetramerized PD-L1 extracellular domain to PD-1-expressing cells: possible application to enhance T cell function

2007 ◽  
Vol 19 (7) ◽  
pp. 881-890 ◽  
Author(s):  
S. Terawaki ◽  
Y. Tanaka ◽  
T. Nagakura ◽  
T. Hayashi ◽  
S. Shibayama ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Function ◽  
Extracellular Domain ◽  
Affinity Binding ◽  
High Affinity Binding ◽  
High Affinity ◽  
T Cell Function

The extracellular domain of the neurokinin-1 receptor is required for high-affinity binding of peptides

Biochemistry ◽  
1992 ◽  
Vol 31 (47) ◽  
pp. 11806-11811 ◽  
Author(s):  
Tung Ming Fong ◽  
Hong Yu ◽  
Ruey Ruey C. Huang ◽  
Catherine D. Strader
Keyword(s):  
Extracellular Domain ◽  
Affinity Binding ◽  
High Affinity Binding ◽  
Neurokinin 1 Receptor ◽  
High Affinity ◽  
Neurokinin 1

scholarly journals NDR1-Dependent Regulation of Kindlin-3 Controls High-Affinity LFA-1 Binding and Immune Synapse Organization

2017 ◽  
Vol 37 (8) ◽  
Author(s):  
Naoyuki Kondo ◽  
Yoshihiro Ueda ◽  
Toshiyuki Kita ◽  
Madoka Ozawa ◽  
Takashi Tomiyama ◽  
...  
Keyword(s):  
T Cell ◽  
Lipid Bilayers ◽  
Single Molecule ◽  
Immunological Synapse ◽  
Cell Attachment ◽  
Cell Receptor ◽  
Affinity Binding ◽  
Low Frequencies ◽  
High Affinity Binding ◽  
High Affinity

ABSTRACT Antigen-specific adhesion between T cells and antigen-presenting cells (APC) during the formation of the immunological synapse (IS) is mediated by LFA-1 and ICAM-1. Here, LFA-1–ICAM-1 interactions were measured at the single-molecule level on supported lipid bilayers. High-affinity binding was detected at low frequencies in the inner peripheral supramolecular activation cluster (SMAC) zone that contained high levels of activated Rap1 and kindlin-3. Rap1 was essential for T cell attachment, whereas deficiencies of ste20-like kinases, Mst1/Mst2, diminished high-affinity binding and abrogated central SMAC (cSMAC) formation with mislocalized kindlin-3 and vesicle transport regulators involved in T cell receptor recycling/releasing machineries, resulting in impaired T cell-APC interactions. We found that NDR1 kinase, activated by the Rap1 signaling cascade through RAPL and Mst1/Mst2, associated with and recruited kindlin-3 to the IS, which was required for high-affinity LFA-1/ICAM-1 binding and cSMAC formation. Our findings reveal crucial roles for Rap1 signaling via NDR1 for recruitment of kindlin-3 and IS organization.

Discovery of COM701, a therapeutic antibody targeting the novel immune checkpoint PVRIG, for the treatment of cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3074-3074 ◽  
Author(s):  
Spencer Liang ◽  
Ofer Levy ◽  
Sudipto Ganguly ◽  
Maya Kotturi ◽  
Ilan Vaknin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Wild Type ◽  
High Affinity ◽  
T Cell Function

3074 Background: While inhibitors of CTLA4 and PD1 have emerged as effective cancer therapies, the majority of treated patients do not derive long term benefit. Employing our computational discovery platform, we discovered PVRIG as an immune suppressive molecule expressed on T and NK cells and identified COM701, an antibody (Ab) targeting human PVRIG that enhances T cell function and anti-tumor responses. Methods: Anti-human PVRIG Ab COM701 was identified as an antagonistic Ab that enhanced T cell function in multiple assays. Antagonistic anti-mouse PVRIG Abs and PVRIG deficient (PVRIG-/-) mice were generated and characterized using syngeneic tumor models. Results: PVRIG was induced upon T cell activation, with long term activation leading to the highest expression. PVRL2 was identified as the ligand for PVRIG, placing PVRIG in the DNAM/TIGIT immunoreceptor axis. Compared to normal adjacent tissues, PVRIG and PVRL2 were both induced in the tumor microenvironment of several human cancers. To target PVRIG for therapeutic intervention, we identified COM701, a high affinity Ab that disrupts the interaction of PVRIG with PVRL2. COM701 enhanced CD8 T cell proliferation and IFN-g production in vitro and had an additive or synergistic effect on T cell activation when further combined with an anti-PD1 or anti-TIGIT Ab. Consistent with a checkpoint function for human PVRIG, mouse PVRIG-/- T cells showed increased function compared to wild type T cells. A surrogate antagonistic anti-mPVRIG Ab reduced growth of CT26 and B16 tumors when combined with an anti-PDL1 Ab in vivo. MC38 tumors also grew slower in PVRIG-/- mice compared to wild type mice and ex vivo analysis pointed to functional differences in anti-cancer immunity. Conclusions: We demonstrated that targeting PVRIG with COM701, a high affinity antagonistic Ab, increased human T cell function. We further showed that PVRIG was induced in the tumor microenvironment and that disruption of PVRIG/PVRL2 interaction resulted in reduced tumor growth in preclinical models. These data demonstrate that PVRIG is a promising target for the treatment of cancer and provide the rationale for COM701 as a potential cancer immunotherapy.

Interleukin-15 (IL-15) Can Replace the IL-2 Signal in IL-2–Dependent Adult T-Cell Leukemia (ATL) Cell Lines: Expression of IL-15 Receptor α on ATL Cells

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4265-4272 ◽  
Author(s):  
Yasuaki Yamada ◽  
Kazuyuki Sugawara ◽  
Tomoko Hata ◽  
Kazuto Tsuruta ◽  
Ryozo Moriuchi ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Affinity Binding ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
High Affinity Binding ◽  
Adult T Cell Leukemia ◽  
High Affinity ◽  
Interleukin 15 ◽  
Α Chain

Abstract Interleukin-15 receptor (IL-15R) and IL-2R have the same β and γ chains, but IL-15R has a specific α chain distinct from that of IL-2Rα, which is indispensable for the high affinity binding of IL-15. In the present study, we examined four IL-2-dependent adult T-cell leukemia (ATL) cell lines for their IL-15R expression. All cell lines bound IL-15, which was not inhibited by a 100-fold excess amount of IL-2, proliferated in response to IL-15 to the same degree as to the stimulation with IL-2, and were maintained without IL-2. The responses to 1L-15 were inhibited by the antibodies against IL-2R β or γ chains but was not by the IL-2R α chain antibody. [125I]–IL-15 exhibited a single high-affinity binding with an apparent kd of 0.17 nmol/L. Reverse transcription–coupled polymerase chain reaction (RT-PCR) showed that the cell lines had the mRNA of IL-15R α. The cell lines also had IL-15 mRNA. Despite the presence of IL-15 mRNA, the cell lines did not secrete IL-15, and the culture supernatants of fresh ATL cells and plasma from the patients did not contain a detectable amount of IL-15 with a few exceptional cases, although fresh ATL cells also responded to IL-15. These results suggest that ATL cells have the complete form of IL-15R and respond to IL-15. Such an IL-15–dependent cell proliferation mechanism might be used in the development of ATL and for the invasion and proliferation of ATL cells in the visceral organs.

scholarly journals Receptors for T cell-replacing factor/interleukin 5. Specificity, quantitation, and its implication.

1988 ◽  
Vol 168 (3) ◽  
pp. 863-878 ◽  
Author(s):  
S Mita ◽  
N Harada ◽  
S Naomi ◽  
Y Hitoshi ◽  
K Sakamoto ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Line ◽  
Binding Sites ◽  
B Cell Lymphoma ◽  
Affinity Binding ◽  
High Affinity Binding ◽  
High Affinity ◽  
Activated B Cells

T cell-replacing factor (TRF)/IL-5 is a glycosylated polypeptide that acts as a key factor for B cell growth and differentiation. Since IL-5 action is probably mediated by specific cell surface receptor(s), we have characterized the binding of IL-5 to cells using biosynthetically [35S]methionine-labeled IL-5 and 125I-IL-5 that had been prepared using Bolton-Hunter reagent. The radiolabeled IL-5 binds specifically to BCL1-B20 (in vitro line) (a murine chronic B cell leukemic cell line previously shown to differentiate into IgM-secreting cells in response to IL-5) within 10 min at 37 degrees C. There are two classes of binding sites with high affinity (Kd = 66 pM) and low affinity (Kd = 12 nM) for IL-5 and an average number of binding sites for high affinity and for low affinity were 400 and 7,500 per cell, respectively. The specificity of binding of radiolabeled IL-5 has been confirmed by demonstrating that only unlabeled IL-5 and anti-IL-5 mAb but not by IL-1, IL-2, IL-3, IFN-gamma, and GM-CSF inhibit radiolabeled IL-5 binding to BCL1-B20 cells. Treatment of surface-bound radiolabeled IL-5 with bivalent crosslinkers identified a membrane polypeptide of Mr 46,500 to which IL-5 is crosslinked. A variety of cell types have been surveyed for the capacity to bind specifically radiolabeled IL-5 with high affinity. BCL1 cells MOPC104E (murine myeloma cell line) expressed IL-5-R, whereas BAL. 17 and L10 A (B cell lymphoma) did not. T cell line, mastocytoma cell line, or macrophage tumor cell line did not display detectable levels of IL-5-R. were hardly detectable on normal resting B cells but were expressed on LPS-activated B cells, fitting the function of IL-5 that acts on activated B cells for their differentiation into Ig-secreting cells. Intriguingly, early B cell lines (J-87 and T-88) that grow in the presence of IL-5 expressed significant but low numbers of high-affinity binding sites for IL-5. The biological effects of IL-5 were mediated by high-affinity binding sites. The identification and characterization of IL-5-R should provide new insight into the apparent diverse biological activities of IL-5.

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