Killer immunoglobulin-like receptors (KIRs) play an essential role in the regulation of natural killer cell functions. KIR genes are highly polymorphic in nature, showing both haplotypic and allelic variations among people. We demonstrated in both in vitro and in vivo models a significant heterogeneity in function among different KIR2DL1 alleles, including their ability to inhibit YT-Indy cells from degranulation, interferon ␥ production, and cytotoxicity against target cells expressing the HLA-Cw6 ligand. Subsequent experiments showed that the molecular determinant was an arginine residue at position 245 (R245) in its transmembrane domain that mechanistically affects both the efficiency of inhibitory signaling and durability of surface expression. Specifically, in comparison with R245-negative alleles, KIR2DL1 that included R245 recruited more Src-homology-2 domaincontaining protein tyrosine phosphatase 2 and -arrestin 2, showed higher inhibition of lipid raft polarization at immune synapse, and had less down-regulation of cell-surface expression upon interaction with its ligand. Thus, our findings provide novel insights into the molecular determinant of KIR2DL1 and conceivably a fundamental understanding of KIR2DL1 allelic polymorphism in human disease susceptibility, transplant outcome, and donor selection. (Blood. 2009;114:5182-5190) IntroductionNatural killer (NK) cells are a part of our immune system that eliminates virally infected cells and tumor cells through cytolytic killing and cytokine secretion. 1 An NK cell's responses to its targets are regulated by the balance of signals generated through various activating and inhibiting receptors. 2,3 NK-cell receptors may be categorized on the basis of their ligand specificity for major histocompatibility complex class I and related molecules. Expression of various combinations of receptors on the surface of NK cells creates a diverse repertoire. 4,5 In humans, one of the most important groups of receptors that regulate NK-cell function is killer immunoglobulin-like receptors (KIRs). 6,7 The KIRs make up a family of diverse glycoproteins encoded by a compact cluster of genes located on human chromosome 19q13.4. 8,9 KIRs expressed at the surface of NK cells regulate their response by interacting with human leukocyte antigen (HLA) class I molecules. The KIR family has both activating and inhibitory receptors. KIR inhibitory receptors suppress NK cells' function using the immunoreceptor tyrosine-based inhibitory motif in their long cytoplasmic tails. Activating KIR receptors have short cytoplasmic tails and do not contain the inhibitory motif.Each of the KIR genes exhibits allelic variation as well as haplotypic variability in terms of the number and types of genes on the haplotypes. 9,10 The allelic variations of KIR genes range from 2 to more than 30. 10 The polymorphisms between the alleles of a given KIR gene can occur in its extracellular, transmembrane, or cytoplasmic domains. Polymorphism at each of these 3 domains has been associated with significant bi...
Killer-cell immunoglobulin-like receptors (KIRs) on natural killer (NK) cells have been linked to a wide spectrum of health conditions such as chronic infections, autoimmune diseases, pregnancy complications, cancers, and transplant failures. A small subset of effector memory T cells also expresses KIRs. Here, we use modern analytic tools including genome-wide and multiplex molecular, phenotypic, and functional assays to characterize the KIR+ T cells in human blood. We find that KIR+ T cells primarily reside in the CD56+ T population that is distinctively DNAM-1high with a genome-wide quiescent transcriptome, short telomere, and limited TCR excision circles. During cytomegalovirus (CMV) reactivation in bone marrow transplant recipients, KIR+CD56+ T cells rapidly expanded in real-time, but not KIR+CD56− T cells or KIR+ NK cells. In CMV+ asymptomatic donors, as much as 50% of CD56+ T cells are KIR+, and most are distinguishably KIR2DL2/3+NKG2C+CD57+. Functionally, the KIR+CD56+ T-cell subset lyses cancer cells and CMVpp65-pulsed target cells in a dual KIR-dependent and TCR-dependent manner. Analysis of metabolic transcriptome confirms the immunological memory status of KIR+CD56+ T cells, in contrast to KIR−CD56+ T cells that are more active in energy metabolism and effector differentiation. KIR−CD56+ T cells have >25-fold higher level of expression of RORC than the KIR+ counterpart and are a previously unknown producer of IL-13 rather than IL-17 in multiplex cytokine arrays. Our data provide fundamental insights intoKIR + T cells biologically and clinically.
Zona pellucida (ZP) is a glycoproteinaceous translucent matrix that surrounds the mammalian oocyte and plays a critical role in the accomplishment of fertilization. In humans, it is composed of 4 glycoproteins designated as ZP1, ZP2, ZP3 and ZP4, whereas mouse ZP is composed of ZP1, ZP2 and ZP3 (Zp4 being a pseudogene). In addition to a variable sequence identity of a given zona protein among various species, human ZP1 and ZP4 are paralogs and mature polypeptide chains share an identity of 47%. Employing either affinity purified native or recombinant human zona proteins, it has been demonstrated that ZP1, ZP3 and ZP4 bind to the capacitated human spermatozoa and induce an acrosome reaction, whereas in mice, ZP3 acts as the putative primary sperm receptor. Human ZP2 only binds to acrosome-reacted spermatozoa and thus may be acting as a secondary sperm receptor. In contrast to O-linked glycans of ZP3 in mice, N-linked glycans of human ZP3 and ZP4 are more relevant for induction of the acrosome reaction. Recent studies suggest that Sialyl-Lewis(x) sequence present on both N- and O-glycans of human ZP play an important role in human sperm-egg binding. There are subtle differences in the downstream signaling events associated with ZP3 versus ZP1/ZP4-mediated induction of the acrosome reaction. For example, ZP3 but not ZP1/ZP4-mediated induction of the acrosome reaction is dependent on the activation of the Gi protein-coupled receptor. Thus, various studies suggest that, in contrast to mice, in humans more than one zona protein binds to spermatozoa and induces an acrosome reaction.
Availability of recombinant porcine proteins will be useful in the development of contraceptive vaccine.
While melanoma remains a challenge for oncologists, possibilities are being continuously explored to fight resistant metastatic melanoma more effectively. Eugenol is reported to inhibit survivin protein in breast cancer cells. Survivin is also overexpressed by melanoma cells, and is known to impart resistance to them against chemotherapy-induced apoptosis. To be able to fight resistant melanoma, we formulated hyaluronic acid (HA)-coated liposomes loaded with an effective combination of anti-melanoma agents (Dacarbazine and Eugenol), using a solvent injection method. Quality-by-Design (QbD) was applied to optimize and obtain a final formulation with the desired quality attributes, and within an acceptable size range. The optimized formulation was then subjected to performance analysis in cell lines. Coated-Dacarbazine Eugenol Liposomes were found to possess 95.08% cytotoxicity at a dacarbazine concentration of 0.5 µg/mL, while Dacarbazine Solution showed only 10.20% cytotoxicity at the same concentration. The number of late apoptotic cells was also found to be much higher (45.16% vs. 8.43%). Furthermore, migration assay and proliferation study also revealed significantly higher inhibition of cell migration and proliferation by Coated-Dacarbazine Eugenol Liposomes, signifying its potential against metastasis. Thus, surface-functionalized dacarbazine- and eugenol-loaded liposomes hold great promise against resistant and aggressive metastatic melanoma, with much less unwanted cytotoxicity and reduced doses of the chemotherapeutic agent.
Foramen Vesalius is a small, variable and an inconstant foramen located in the greater wing of sphenoid, anteromedial to the foramen ovale, in the middle cranial fossa. This foramen is also known as emissary sphenoidal foramen as it transmits a small emissary vein which drains Cavernous sinus. The importance of this foramen lies in the fact that an infected thrombus from an extracranial source may reach cavernous sinus. The present study was undertaken to observe the incidence of foramen Vesalius in the adult human crania in north India. For this purpose, 200 macerated skulls of unknown age and sex were observed. These skulls were obtained from the departments of Anatomy in
Citation Gupta SK, Srinivasan VA, Suman P, Rajan S, Nagendrakumar SB, Gupta N, Shrestha A, Joshi P, Panda AK. Contraceptive vaccines based on the zona pellucida glycoproteins for dogs and other wildlife population management. Am J Reprod Immunol 2011; 66: 51–62 Zona pellucida (ZP) glycoproteins, by virtue of their critical role in fertilization, have been proposed as candidate antigens for the development of contraceptive vaccines. In this review, the potential of a ZP‐based contraceptive vaccine for the management of wildlife population, with special reference to street dogs, is discussed. Immunization of various animal species, including female dogs, with native porcine ZP led to inhibition of fertility, which was associated with the ovarian dysfunction. Immunization of female dogs with Escherichia coli‐expressed recombinant dog ZP glycoprotein‐3 (ZP3) either coupled to diphtheria toxoid or expressed as fusion protein with ‘promiscuous’ T non‐B‐cell epitope of tetanus toxoid also led to inhibition of fertility. To improve the contraceptive efficacy of ZP‐based contraceptive vaccine, various groups are working on improving the immunogen, use of DNA vaccine as prime‐boost strategy, and delivering the zona proteins/peptides presented on either virus‐like particles or entrapped in microsphere. Host‐specific live vectors such as ectromelia virus and cytomegalovirus have also been used to deliver mouse ZP3 in mice. Various studies show the enormous potential of the ZP‐based vaccine for the management of wildlife population, where permanent sterilization may be desirable.
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