Biomedical subjects

Emma Teixeiro

Publications and source records attributed to Emma Teixeiro.

5 recordsLinked to original sources

PubMed2006

Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling.

A healthy individual can mount an immune response to exogenous pathogens while avoiding an autoimmune attack on normal tissues. The ability to distinguish between self and non-self is called 'immunological tolerance' and, for T lymphocytes, involves the generation of a diverse pool of functional T cells through positive selection and the removal of overtly self-reactive thymocytes by negative selection during T-cell ontogeny. To elucidate how thymocytes arrive at these cell fate decisions, here we have identified ligands that define an extremely narrow gap spanning the threshold that distinguishes positive from negative selection. We show that, at the selection threshold, a small increase in ligand affinity for the T-cell antigen receptor leads to a marked change in the activation and subcellular localization of Ras and mitogen-activated protein kinase (MAPK) signalling intermediates and the induction of negative selection. The ability to compartmentalize signalling molecules differentially in the cell endows the thymocyte with the ability to convert a small change in analogue input (affinity) into a digital output (positive versus negative selection) and provides the basis for establishing central tolerance.

Animals↗

PubMed2004

T cell division and death are segregated by mutation of TCRbeta chain constant domains.

We have studied the role of the T cell receptor (TCR) beta chain transmembrane and cytoplasmic domains (betaTM/Cyto) in T cell signaling. Upon antigen stimulation, T lymphocytes expressing a TCR with mutant and betaTM and Cyto domains accumulate in large numbers and are specifically defective in undergoing activation-induced cell death (AICD). The mutant TCR poorly recruits the protein adaptor Carma-1 and is subsequently impaired in activating NF-kappaB. This signaling defect leads to a reduced expression of Fas ligand (FasL) and to a reduction in AICD. These beta chain domains are involved in discriminating cell division and apoptosis.

Amino Acid Sequence↗

PubMed2004

Hydrocortisone and deflazacort induce different effects on vitamin D receptor level increase produced by 1,25-dihydroxyvitamin D3 in rat osteoblast-like UMR-106 cells.

OBJECTIVE: The homologous upregulation produced by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on vitamin D receptor (VDR) levels, and the effects produced by the heterologous agents hydrocortisone or deflazacort, alone or in conjunction with this vitamin D metabolite, were studied in rat osteoblastic UMR-106 osteosarcoma cells. METHODS: VDR were determined by binding analysis (Bmax and dissociation constant). VDR mRNA expression levels were measured by Northern blot analysis. RESULTS: Incubation with 10 nM 1,25(OH)2D3 produced a significant increase in Bmax with respect to ethanol-treated cells (100.2 +/- 13.2 vs 11.4 +/- 4.8 fmol 3H-1,25(OH)2D3 bound/mg protein) together with a significant increase in VDR mRNA expression (483 +/- 170% vs 100%). The addition of 10 nM hydrocortisone to 1,25(OH)2D3 produced a significant decrease in Bmax (from 100.2 +/- 13.2 to 44 +/- 5.6), with mRNA levels similar to those of basal conditions (116 +/- 25% vs 100%). However, the addition of 10 nM deflazacort did not reduce the activation in Bmax produced by 1,25(OH)2D3 (92.4 +/- 16 vs 100.2 +/- 13.2), maintaining the increase in mRNA levels (430 +/- 10% vs 483 +/- 170%). If 10 nM hydrocortisone or 10 nM deflazacort was added to UMR-106 cells without 1,25(OH)2D3, a similar increase was observed in Bmax with respect to basal conditions (20.4 +/- 1.3 or 20.9 +/- 1.6 vs 11.4 +/- 4.8 in control cells), but hydrocortisone did not produce any significant variation in mRNA VDR levels, while deflazacort itself produced an increase in VDR mRNA expression. CONCLUSION: Our findings of different actions produced by hydrocortisone and deflazacort on the increase of VDR levels produced by 1,25(OH)2D3 could explain some of the different actions produced by both antiinflammatory medications on bone metabolism.

Animals↗

PubMed2004

CD8+ T cells oligoclonally expanded in synovial fluid at onset of spondyloarthropathy selectively proliferate in response to self-antigens: characterization of cell specificities in nonclonal populations.

OBJECTIVE: To characterize putative T cells responsible for the pathogenesis of spondyloarthropathies (SpA). METHODS: T cells from synovial fluid (SF) and peripheral blood lymphocytes from a patient with chronic ankylosing spondylitis and a patient at the onset of SpA were analyzed for the size of the ss-chain complementarity-determining region 3 to evaluate the degree of clonality. To assess their putative role in triggering disease, immortalized local T cells were tested in lymphocyte proliferation assays against a restricted panel of cell lines. RESULTS: At disease onset, expansions were detected only in the SF CD8+ T cell subset. As well, SF CD8+ T cells sharing an expanded clonotype (TCR-BV17-J2S1) selectively proliferated when stimulated with autologous-presenting cells. The search for sequence similarities with the expanded clonotype revealed a high homology with the major clonotype in response to influenza A matrix peptide M58-66. CONCLUSION: A CD8+ T cell-mediated antigen-driven mechanism seems to be responsible in the pathogenesis of SpA. Immune response to viral antigens (e.g., from influenza) could be the initiating event in seronegative arthropathies. The combination of spectratyping with RT-PCR and specific Southern blot for the expanded clonotypes on cells derived from mixed lymphocyte cultures was useful to evaluate the proliferative responses of in vivo-expanded cells and to assess T cells involved in the pathogenesis of SpA.

Adult↗

PubMed2001

T cell receptor-mediated signal transduction controlled by the beta chain transmembrane domain: apoptosis-deficient cells display unbalanced mitogen-activated protein kinases activities upon T cell receptor engagement.

The bases that support the versatility of the T cell receptor (TCR) to generate distinct T cell responses remain unclear. We have previously shown that mutant cells in the transmembrane domain of TCRbeta chain are impaired in TCR-induced apoptosis but are not affected in other functions. Here we describe the biochemical mechanisms by which this mutant receptor supports some T cell responses but fails to induce apoptosis. Extracellular signal-regulated protein kinase (ERK) is activated at higher and more sustained levels in TCRbeta-mutated than in wild type cells. Conversely, activation of both c-Jun N-terminal kinase and p38 mitogen-activated protein kinase is severely reduced in mutant cells. By attempting to link this unbalanced induction to altered upstream events, we found that ZAP-70 is normally activated. However, although SLP-76 phosphorylation is normally induced, TCR engagement of mutant cells results in lower tyrosine phosphorylation of LAT but in higher tyrosine phosphorylation of Vav than in wild type cells. The results suggest that an altered signaling cascade leading to an imbalance in mitogen-activated protein kinase activities is involved in the selective impairment of apoptosis in these mutant cells. Furthermore, they also provide new insights in the contribution of TCR to decipher the signals that mediate apoptosis distinctly from proliferation.

Antigens, CD↗