scholarly journals The Total Synthesis of Proposed Immunoactive Glycolipids from S. Pneumoniae and a Re-evaluation of Their Immunological Activity

2021 ◽  
Author(s):  
Seyed Iraj Sadraei ◽  
Greg Yousif ◽  
S. Maryamdokht Taimoory ◽  
Emmanuel Igbokwe ◽  
Samaneh Mehri ◽  
...  
Keyword(s):  
T Cell ◽  
Total Synthesis ◽  
T Cell Receptor ◽  
Mammalian Species ◽  
White Blood Cells ◽  
Computational Modelling ◽  
Cell Receptor ◽  
Binary Complex ◽  
Inkt Cells ◽  
High Degree

<p>Invariant natural killer T cells (iNKT), a subclass of white blood cells, are responsible for the production of pro-inflammatory cytokines which induce a systemic immune response. They are distinctive in having an invariant T-cell receptor that recognizes glycolipid antigens presented by the class I major histocompatibility complex-related protein CD1d, which is conserved across multiple mammalian species in a class of proteins well-renowned for their high degree of polymorphism. This receptor’s first identified antigen is the potent KRN7000, a glycosphingolipid isolated from bacteria that were found on a Japanese marine sponge. The corresponding terrestrial antigen remained unidentified until quite recently, when diacylglycerol-containing glycolipids, reported to activate iNKT cells, were isolated from <i>Streptococcus pneumoniae</i>. We report the total synthesis and immunological re-evaluation of these two glycolipids. The compounds are unable to activate iNKT cells. Computational modelling shows that these ligands, while being capable of interacting with the CD1d receptor, create a different surface for the binary complex that makes formation of the ternary complex with the iNKT T-cell receptor difficult. Together these results suggest that the reported activity might have been due to an impurity in the original isolated sample, and highlights the importance of taking care when reporting biological activity from isolated natural products.<b></b></p>

scholarly journals The Total Synthesis of Proposed Immunoactive Glycolipids from S. Pneumoniae and a Re-evaluation of Their Immunological Activity

2021 ◽  
Author(s):  
Seyed Iraj Sadraei ◽  
Greg Yousif ◽  
S. Maryamdokht Taimoory ◽  
Emmanuel Igbokwe ◽  
Samaneh Mehri ◽  
...  
Keyword(s):  
T Cell ◽  
Total Synthesis ◽  
T Cell Receptor ◽  
Mammalian Species ◽  
White Blood Cells ◽  
Computational Modelling ◽  
Cell Receptor ◽  
Binary Complex ◽  
Inkt Cells ◽  
High Degree

<p>Invariant natural killer T cells (iNKT), a subclass of white blood cells, are responsible for the production of pro-inflammatory cytokines which induce a systemic immune response. They are distinctive in having an invariant T-cell receptor that recognizes glycolipid antigens presented by the class I major histocompatibility complex-related protein CD1d, which is conserved across multiple mammalian species in a class of proteins well-renowned for their high degree of polymorphism. This receptor’s first identified antigen is the potent KRN7000, a glycosphingolipid isolated from bacteria that were found on a Japanese marine sponge. The corresponding terrestrial antigen remained unidentified until quite recently, when diacylglycerol-containing glycolipids, reported to activate iNKT cells, were isolated from <i>Streptococcus pneumoniae</i>. We report the total synthesis and immunological re-evaluation of these two glycolipids. The compounds are unable to activate iNKT cells. Computational modelling shows that these ligands, while being capable of interacting with the CD1d receptor, create a different surface for the binary complex that makes formation of the ternary complex with the iNKT T-cell receptor difficult. Together these results suggest that the reported activity might have been due to an impurity in the original isolated sample, and highlights the importance of taking care when reporting biological activity from isolated natural products.<b></b></p>

scholarly journals The Total Synthesis of Proposed Immunoactive Glycolipids from S. Pneumoniae and a Re-evaluation of Their Immunological Activity

2021 ◽  
Author(s):  
Seyed Iraj Sadraei ◽  
Greg Yousif ◽  
S. Maryamdokht Taimoory ◽  
Maryam Kosar ◽  
Samaneh Mehri ◽  
...  
Keyword(s):  
T Cell ◽  
Total Synthesis ◽  
T Cell Receptor ◽  
Mammalian Species ◽  
Computational Modelling ◽  
Cell Receptor ◽  
Binary Complex ◽  
Inkt Cells ◽  
High Degree ◽  
Killer T Cells

Invariant natural killer T cells (iNKT) are responsible for the production of pro-inflammatory cytokines which induce a systemic immune response. They are distinctive in possessing an invariant T-cell receptor that recognizes glycolipid antigens presented by the class I major histocompatibility complex-related protein CD1d, conserved across multiple mammalian species in a class of proteins well-renowned for their high degree of polymorphism. This receptor’s first identified antigen is the potent α-galactose ceramide, KRN7000, a glycosphingolipid isolated from bacteria that were found on a Japanese marine sponge. The corresponding terrestrial antigen remained unidentified until quite recently, when diacylglycerol-containing glycolipids, reported to activate iNKT cells, were isolated from Streptococcus pneumoniae. We report the total synthesis and immunological re-evaluation of these two glycolipids. The compounds are unable to meaningfully activate iNKT cells. Computational modelling shows that these ligands, while being capable of interacting with the CD1d receptor, create a different surface for the binary complex that makes formation of the ternary complex with the iNKT T-cell receptor difficult. Together these results suggest that the reported activity might have been due to an impurity in the original isolated sample and highlights the importance of taking care when reporting biological activity from isolated natural products.

scholarly journals The adaptor molecule SAP plays essential roles during invariant NKT cell cytotoxicity and lytic synapse formation

Blood ◽  
2013 ◽  
Vol 121 (17) ◽  
pp. 3386-3395 ◽  
Author(s):  
Rupali Das ◽  
Hamid Bassiri ◽  
Peng Guan ◽  
Susan Wiener ◽  
Pinaki P. Banerjee ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Synapse Formation ◽  
Cell Receptor ◽  
Inkt Cells ◽  
Nkt Cell ◽  
Adaptor Molecule ◽  
Key Points ◽  
Immunologic Synapse ◽  
Invariant Nkt Cell

Key Points The adaptor molecule SAP is required for T-cell receptor-induced iNKT cell killing of T- and B-cell targets. SAP-deficient iNKT cells adhere poorly to T-cell lymphoid targets and exhibit reduced polarization of lytic machinery to the immunologic synapse.

A divergent approach to the synthesis of iGb3 sugar and lipid analogues via a lactosyl 2-azido-sphingosine intermediate

2014 ◽  
Vol 12 (17) ◽  
pp. 2729-2736 ◽  
Author(s):  
Janice M. H. Cheng ◽  
Emma M. Dangerfield ◽  
Mattie S. M. Timmer ◽  
Bridget L. Stocker
Keyword(s):  
T Cell ◽  
Natural Killer ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Inkt Cells ◽  
Invariant Natural Killer ◽  
Natural Killer T

Isoglobotrihexosylceramide (iGb3, 1) is an immunomodulatory glycolipid that binds to CD1d and is presented to the T-cell receptor (TCR) of invariant natural killer T (iNKT) cells.

scholarly journals Ets1 Promotes the Differentiation of Post-Selected iNKT Cells through Regulation of the Expression of Vα14Jα18 T Cell Receptor and PLZF

2021 ◽  
Vol 22 (22) ◽  
pp. 12199
Author(s):  
Ya-Ting Chuang ◽  
Wan-Chu Chuang ◽  
Chih-Chun Liu ◽  
Chia-Wei Liu ◽  
Yu-Wen Huang ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Target Genes ◽  
Cell Receptor ◽  
Mechanisms Of Action ◽  
Inkt Cells ◽  
Genome Wide ◽  
Invariant Natural Killer ◽  
Multiple Stages ◽  
Molecular Picture

The transcription factor Ets1 is essential for the development/differentiation of invariant Natural Killer T (iNKT) cells at multiple stages. However, its mechanisms of action and target genes in iNKT cells are still elusive. Here, we show that Ets1 is required for the optimal expression of the Vα14Jα18 T cell receptor (TCR) in post-selected thymic iNKT cells and their immediate differentiation. Ets1 is also critical for maintaining the peripheral homeostasis of iNKT cells, which is a role independent of the expression of the Vα14Jα18 TCR. Genome-wide transcriptomic analyses of post-selected iNKT cells further reveal that Ets1 controls leukocytes activation, proliferation differentiation, and leukocyte-mediated immunity. In addition, Ets1 regulates the expression of ICOS and PLZF in iNKT cells. More importantly, restoring the expression of PLZF and the Vα14Jα18 TCR partially rescues the differentiation of iNKT cells in the absence of Ets1. Taken together, our results establish a detailed molecular picture of how Ets1 regulates the stepwise differentiation of iNKT cells.

scholarly journals The naive T-cell receptor repertoire has an extremely broad distribution of clone sizes

2019 ◽  
Author(s):  
Peter C. de Greef ◽  
Theres Oakes ◽  
Bram Gerritsen ◽  
Mazlina Ismail ◽  
James M. Heather ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Computational Modelling ◽  
Cell Receptor ◽  
Sequencing Data ◽  
Receptor Repertoire ◽  
Cell Clones ◽  
Tcr Repertoire ◽  
Naïve T Cell ◽  
Naive T Cell

AbstractThe human naive T-cell receptor (TCR) repertoire is extremely diverse and accurately estimating its distribution is challenging. We address this challenge by combining a quantitative sequencing protocol of TCRA and TCRB sequences with computational modelling. We observed the vast majority of TCR chains only once in our samples, confirming the enormous diversity of the naive repertoire. However, a substantial number of sequences were observed multiple times within samples, and we demonstrated that this is due to expression by many cells in the naive pool. We reason that α and β chains are frequently observed due to a combination of selective processes and summation over multiple clones expressing these chains. We test the contribution of both mechanisms by predicting samples from phenomenological and mechanistically modelled repertoire distributions. By comparing these with sequencing data, we show that frequently observed chains are likely to be derived from multiple clones. Still, a neutral model of T-cell homeostasis cannot account for the observed distributions. We conclude that the data are only compatible with distributions of many small clones in combination with a sufficient number of very large naive T-cell clones, the latter most likely as a result of peripheral selection.

scholarly journals T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse

2011 ◽  
Vol 208 (6) ◽  
pp. 1279-1289 ◽  
Author(s):  
Amy E. Moran ◽  
Keli L. Holzapfel ◽  
Yan Xing ◽  
Nicole R. Cunningham ◽  
Jonathan S. Maltzman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Antigen Receptor ◽  
Cell Receptor ◽  
Treg Cells ◽  
Receptor Activation ◽  
Early Gene ◽  
Inkt Cells ◽  
Tcr Signals

The ability of antigen receptors to engage self-ligands with varying affinity is crucial for lymphocyte development. To further explore this concept, we generated transgenic mice expressing GFP from the immediate early gene Nr4a1 (Nur77) locus. GFP was up-regulated in lymphocytes by antigen receptor stimulation but not by inflammatory stimuli. In T cells, GFP was induced during positive selection, required major histocompatibility complex for maintenance, and directly correlated with the strength of T cell receptor (TCR) stimulus. Thus, our results define a novel tool for studying antigen receptor activation in vivo. Using this model, we show that regulatory T cells (Treg cells) and invariant NKT cells (iNKT cells) perceived stronger TCR signals than conventional T cells during development. However, although Treg cells continued to perceive strong TCR signals in the periphery, iNKT cells did not. Finally, we show that Treg cell progenitors compete for recognition of rare stimulatory TCR self-ligands.

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