PubMed Health⌕ Search

Biomedical subjects

Cosima T Baldari

Publications and source records attributed to Cosima T Baldari.

27 records · Page 2Linked to original sources
PubMed2003

The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms.

Helicobacter pylori toxin, VacA, damages the gastric epithelium by erosion and loosening of tight junctions. Here we report that VacA also interferes with T cell activation by two different mechanisms. Formation of anion-specific channels by VacA prevents calcium influx from the extracellular milieu. The transcription factor NF-AT thus fails to translocate to the nucleus and activate key cytokine genes. A second, channel-independent mechanism involves activation of intracellular signaling through the mitogen-activated protein kinases MKK3/6 and p38 and the Rac-specific nucleotide exchange factor, Vav. As a consequence of aberrant Rac activation, disordered actin polymerization is stimulated. The resulting defects in T cell activation may help H. pylori to prevent an effective immune response leading to chronic colonization of its gastric niche.

Active Transport, Cell Nucleus↗
PubMed2003

T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions.

Atherosclerotic lesions are infiltrated by macrophages and T lymphocytes, potentially reactive to pathogens. We studied in vivo activated T lymphocytes that infiltrate atherosclerotic plaques of Helicobacter pylori-infected patients with or without anti-Chlamydia pneumoniae antibodies. In all atherosclerotic lesions, T helper type 1 (Th1) cells were predominant. C. pneumoniae-specific T cells were detected only in the plaques of anti-C. pneumoniae seropositive patients, whereas H. pylori-specific T cells were found in the gastric mucosa but not in the plaques of the same patients. Plaque-derived Th1 cells expressed cytotoxicity, proapoptotic activity, and help for monocyte tissue factor production. Although multifactorial, atherosclerosis can be regarded as a Th1-driven immunopathological condition.

Antibodies, Bacterial↗
PubMed2003

Extensive temporally regulated reorganization of the lipid raft proteome following T-cell antigen receptor triggering.

Signalling by immunoreceptors is orchestrated at specific plasma membrane microdomains, referred to as lipid rafts. Here we present a proteomics approach to the temporal analysis of protein association with lipid rafts following T-cell antigen receptor (TCR) triggering. We show that TCR engagement promotes the temporally regulated recruitment of proteins participating in the TCR signalling cascade to lipid rafts. Furthermore, TCR triggering results in profound modifications in the composition of lipid rafts involving a number of proteins associated either directly or indirectly with both plasma and intracellular membranes. Raft-associated proteins can be clustered according to their temporal profile of raft association. The data identify lipid rafts as highly dynamic structures and reveal a dramatic impact of surface TCR triggering not only on components of the TCR signalling machinery but also on proteins implicated in a number of diverse cellular processes.

Animals↗
PubMed2003

Normal B-1 cell development but defective BCR signaling in Lck-/- mice.

Mature B cells are grouped into two major subsets, B-1 and B-2, believed to derive from separate lineages. We have recently shown that B-1 cells, which are characterized by CD5 surface expression, specifically exhibit significant levels of the tyrosine kinase Lck in man. Here we show that also in mice Lck expression is restricted to B-1 cells and address the potential role of Lck in B-1 cell development and activation. Using as a model an Lck-/- mouse, we show that, while dispensable for B-1 cell development, Lck is required for full and sustained activation of the tyrosine phosphorylation and MAP kinase cascades triggered by the BCR in CD5+, B-1 cells. The data suggest a potential role for Lck in the achievement of the higher activation threshold required for productive BCR signaling in B-1 as compared to B-2 cells.

Animals↗
PubMed2003

T cell costimulation by the hepatitis C virus envelope protein E2 binding to CD81 is mediated by Lck.

Binding of the hepatitis C virus (HCV) envelope protein E2 to CD81 provides a costimulatory signal for human T cells. This phenomenon may play a role in liver damage and autoimmune manifestations associated with HCV infection. Here we show that cross-linking of CD81 by HCV E2 induced a calcium flux in T cells that depends on Lck since it was blocked by PP1 and absent in Lck-deficient Jurkat T cells. In wild-type Jurkat cells, Lck was activated by CD81 cross-linking, and CD81, like Lck, was found in lipid rafts. Indeed, the integrity of the raft compartment was required for the induction of a calcium flux by E2, since methyl-beta-cyclodextrin abolished this response. A requirement for TCR/CD3 expression was indicated by the absence of a calcium flux following E2 stimulation of TCR/CD3-deficient Jurkat cells. CD81 cross-linking increased and prolonged the anti-CD3-induced tyrosine phosphorylation of TCR1 and of other proteins, indicating that the CD81-mediated signal converges with the TCR/CD3 signaling cascade at its most upstream step. In conclusion, we propose that the costimulatory effects of HCV E2 on T cells depend on CD81 cross-linking that activates Lck through raft aggregation and thus leads to enhanced TCR signaling.

Antigens, CD↗
PubMed2002

The p66Shc longevity gene is silenced through epigenetic modifications of an alternative promoter.

The mammal Shc locus encodes three overlapping isoforms (46, 52, and 66 kDa) that differ in the length of their N-terminal regions. p46/p52Shc and p66Shc have been implicated, respectively, in the cytoplasmic propagation of growth and apoptogenic signals. Levels of p66Shc expression correlate with life span duration in mice. p46Shc and p52Shc are ubiquitously expressed, whereas p66Shc is expressed in a cell lineage-specific fashion. However, the mechanisms underlying the regulation of Shc protein expression are unknown. Here we report the identification of two alternative promoters, driving the transcription of two mRNAs coding for p46/p52Shc and p66Shc. We show that treatment with an inhibitor of histone deacetylases or with a demethylating agent results in induction of p66Shc expression in cells that normally do not express this isoform but leaves the levels of the two other isoforms unchanged. Moreover, analysis of the methylation pattern of the p66Shc promoter in a panel of primary and immortalized human cells showed inverse correlation between p66Shc expression and methylation density of its promoter. These results identify histone deacetylation and cytosine methylation as the mechanisms underlying p66Shc silencing in nonexpressing cells.

3T3 Cells↗
PubMed2002

F-actin dynamics control segregation of the TCR signaling cascade to clustered lipid rafts.

Following ligand binding the TCR segregates to plasma membrane microdomains, termed lipid rafts, characterized by a highly ordered lipid structure favoring partitioning of glycosyl phosphatidyl inositol-linked costimulatory receptors and acylated signaling molecules. Here we show that the inducible association of the TCR and key signaling proteins with lipid rafts is dependent on the actin cytoskeleton through a mechanism involving raft coalescence. Although lipid rafts are required for full activation of the TCR-dependent tyrosine phosphorylation cascade and sustained signaling, triggering of TCR-proximal events, including Fyn activation and a first wave of Vav phosphorylation, is independent of lipid rafts, while a second wave of raft-dependent Vav phosphorylation occurs after raft coalescence, as also supported by the finding that Vav is phosphorylated in response to lipid raft clustering by GM1 aggregation. The constitutive association found between Vav and the CD3zeta chain suggests a model whereby the TCR-associated signaling machinery initiates raft aggregation by promoting F-actin reorganization, which permits full activation of the tyrosine phosphorylation cascade, further reorganization of the actin cytoskeleton and sustained signaling, leading to cell activation.

Actins↗
PubMed2001

Nonsteroidal anti-inflammatory drugs suppress T-cell activation by inhibiting p38 MAPK induction.

In addition to antagonizing inflammation by inhibiting the activity of cyclooxygenases (COX), nonsteroidal anti-inflammatory drugs (NSAID) block T-cell activation. The immunosuppressant activity of NSAID correlates with their ability to block transcription factors required for the expression of inducible response genes triggered by T-cell antigen receptor (TCR) engagement. Whereas the inhibition of nuclear factor-kappaB by aspirin and sodium salicylate can be partly accounted for by their binding to IkappaB kinase-beta, the broad range of transcriptional targets of NSAID suggests that the products of COX activity might affect one or more among the early steps in the TCR-signaling cascade. Here we show that the inhibition of NF-AT activation by NSAID correlates with a selective inhibition of p38 MAP kinase induction. The suppression of TCR-dependent p38 activation by NSAID can be fully overcome by prostaglandin E(2), underlining the requirement for COX activity in p38 activation. Furthermore, the inhibition of COX-1 results in defective induction of the COX-2 gene, which behaves as an early TCR responsive gene. The data identify COX-1 and COX-2 as integral and sequential components of TCR signaling to p38 and contribute to elucidate the molecular basis of immunosuppression by NSAID.

Anti-Inflammatory Agents, Non-Steroidal↗