TIGIT is an inhibitory receptor expressed on lymphocytes and can inhibit T cells by preventing CD226 co-stimulation through interactions in cis or through competition of shared ligands. Whether TIGIT ...directly delivers cell-intrinsic inhibitory signals in T cells remains unclear. Here we show, by analysing lymphocytes from matched human tumour and peripheral blood samples, that TIGIT and CD226 co-expression is rare on tumour-infiltrating lymphocytes. Using super-resolution microscopy and other techniques, we demonstrate that ligation with CD155 causes TIGIT to reorganise into dense nanoclusters, which coalesce with T cell receptor (TCR)-rich clusters at immune synapses. Functionally, this reduces cytokine secretion in a manner dependent on TIGIT's intracellular ITT-like signalling motif. Thus, we provide evidence that TIGIT directly inhibits lymphocyte activation, acting independently of CD226, requiring intracellular signalling that is proximal to the TCR. Within the subset of tumours where TIGIT-expressing cells do not commonly co-express CD226, this will likely be the dominant mechanism of action.
One mechanism by which monoclonal antibodies (mAb) help treat cancer or autoimmune disease is through triggering antibody-dependent cellular cytotoxicity (ADCC)
CD16 on Natural Killer (NK) cells. ...Afucosylation is known to increase the affinity of mAbs for CD16 on NK cells and here, we set out to assess how mAb afucosylation affects the dynamics of NK cell interactions, receptor expression and effector functions. An IgG1 version of a clinically important anti-CD20 mAb was compared to its afucosylated counterpart (anti-CD20-AF). Opsonization of CD20-expressing target cells, 721.221 or Daudi, with anti-CD20-AF increased NK cell cytotoxicity and IFNγ secretion, compared to anti-CD20. The afucosylated mAb also caused a more rapid and greater loss of CD16 from NK cell surfaces. Loss of CD16 has recently been shown to be important for NK cell detachment and sequential engagement of multiple target cells. Here, live-cell time-lapse microscopy of individual cell-cell interactions in an aqueous environment and a three-dimensional matrix, revealed that anti-CD20-AF induced more rapid killing of opsonized target cells. In addition, NK cells detached more quickly from target cells opsonized with anti-CD20-AF compared to anti-CD20, which increased engagement of multiple targets and enabled a greater proportion of NK cells to perform serial killing. Inhibition of CD16 shedding with TAPI-0 led to reduced detachment and serial killing. Thus, disassembly of the immune synapse caused by loss of cell surface CD16 is a factor determining the efficiency of ADCC and antibody afucosylation alters the dynamics of intercellular interactions to boost serial killing.
Intracellular pathogens are differentially sensed by the compartmentalized host immune system. Nevertheless, gene expression studies of infected cells commonly average the immune responses, ...neglecting the precise pathogen localization. To overcome this limitation, we dissected the transcriptional immune response to Shigella flexneri across different infection stages in bulk and single cells. This identified six distinct transcriptional profiles characterizing the dynamic, multilayered host response in both bystander and infected cells. These profiles were regulated by external and internal danger signals, as well as whether bacteria were membrane bound or cytosolic. We found that bacterial internalization triggers a complex, effector-independent response in bystander cells, possibly to compensate for the undermined host gene expression in infected cells caused by bacterial effectors, particularly OspF. Single-cell analysis revealed an important bacterial strategy to subvert host responses in infected cells, demonstrating that OspF disrupts concomitant gene expression of proinflammatory, apoptosis, and stress pathways within cells. This study points to novel mechanisms through which bacterial internalization, localization, and injected effectors orchestrate immune response transcriptional signatures.
Successful diversity programs at colleges and universities level the playing field for women and minorities by addressing their needs and teaching undergraduates the unwritten rules of academic ...science. Rey discusses these various programs and their results.
Using an automated coupled colorimetric assay for the
Escherichia coli cyclopropane fatty acid synthase (CFAS), we have screened an academic chemical library of 3040 compounds, to identify new ...inhibitors of this enzyme. We identified 8 compounds as potent inhibitors of this enzyme, with IC
50 ranging from 1 to 10 µM, in the presence of 750 µM
S-adenosyl-
l-methionine and 1 mg/mL phospholipids. We conducted kinetic analyses of the inhibition of the CFAS using dioctylamine and three inhibitors identified in this report: sinefungin,
1, a synthetic
S-adenosyl-
l-homocysteine analog,
2, and an indoloquinolizine derivative,
3. The inhibition patterns observed were interpreted assuming that the
E. coli CFAS operated via an ordered Bi Bi mechanism with binding of
S-adenosyl-
l-methionine first. Dioctylamine was the most potent inhibitor with a competitive inhibition constant of 130 nM with respect to the phospholipids. Compound
2 bound to the two substrate-binding sites of the enzyme suggesting that it acted as a bisubstrate analog (apparent inhibition constant,
K
I
=
6 µM). Compound
2 was also found to completely inhibit cyclopropanation of the phospholipids in growing
E. coli cells, at 150 µM. This molecule is thus the first inhibitor of a cyclopropane synthase that is active in vivo, contrary to sinefungin and other analogs that are only active on the isolated enzyme.
Cette étude avait pour but d’évaluer prospectivement sur six mois le lien entre la rétropulsion des personnes âgées et le risque de chute. La population était constituée de 30 sujets, de plus de ...65ans, hospitalisés en service de gériatrie. La rétropulsion a été évaluée à j+0 à l’aide de l’échelle Backward Disequilibrium Scale qui a permis de définir deux groupes : un groupe non rétropulseur de 11 patients (score<3) et un groupe rétropulseur de 19 patients (score ≥3). Le nombre de chutes a été évalué à un et six mois. Nos résultats ont montré qu’il n’existe pas de différence significative entre les deux groupes sur la présence de chute à un mois (p=0,2685). À six mois une différence significative a été mise en évidence (p=0,02387). Nous avons observé également une corrélation entre le degré de rétropulsion et le nombre de chutes à six mois (p=0,0399 et rho=0,428). Ces résultats ont montré un lien entre la rétropulsion et le nombre de chutes. Il est donc important d’évaluer précisément ce trouble afin d’avoir une rééducation adaptée.
II.
It was a prospective evaluation on six months of the link between backward disequilibrium in geriatric population and falls. The population was consisted in 30 patients aged more than 65 years old. The population was evaluated with the Backward Disequilibrium Scale. The Backward Disequilibrium Scale allowed to separate two groups. One group “not backward disequilibrium” (score<3) constituted by 11 patients. The other group “backward disequilibrium” (score≥3) made up of 19 patients. Number of falls was measured at days+1 month and days+6 months. Although results of our study did not show difference between patients with backward disequilibrium and patients without backward disequilibrium concerning falls at day +1 month (P=0.269), this difference became significant at day+6 months (P=0.024). There was also a correlation between backward disequilibrium level and number of falls at six months (P=0.040 and rho=0.428). Results showed a link between backward disequilibrium and falls. So, that should be important to evaluate precisely backward disequilibrium in order to have an efficient rehabilitation.
II.
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