Biomedical subjects

Leandro J Carreño

Publications and source records attributed to Leandro J Carreño.

3 recordsLinked to original sources

PubMed2006

Modulation of T cell function by TCR/pMHC binding kinetics.

The interaction between the T cell receptor (TCR) and the peptide-MHC complex (pMHC) at the interface between the T cell and the antigen presenting cell (APC) is the main event controlling the specificity of antigen recognition by T cells. It is thought that TCR/pMHC binding kinetics are critical for the selection of the T cell repertoire in the thymus, as well as the activation of mature T cells in the periphery. One of the binding parameters that conditions T cell activation by pMHC ligands is the half-life of the TCR/pMHC interaction. This kinetic parameter is highly significant for the regulation of T cell activation and therefore determines the capacity of T cells to respond against pathogen- and tumor-derived antigens, avoiding self-reactivity. Several studies support the notion that T cells are activated only by TCR/pMHC interactions that are above a threshold of half-life. pMHC complexes that bind TCRs with half-lives below that threshold behave as null or antagonistic ligands. However, since prolonged half-lives can also impair T cell activation, there seems to be a ceiling for the TCR/pMHC half life that leads to efficient activation of T cells. According to these observations, efficient T cell activation would require an optimal half-life of TCR/pMHC interaction. These kinetic restrictions for T cell activation are important to generate a protective adaptive immune response minimizing cross-reactivity against self-constituents. The nature of the TCR/pMHC interaction defines in the thymus whether a thymocyte develops into a mature T cell or is eliminated by apoptosis. In addition, the kinetics of TCR/pMHC binding can determine the type of response shown by mature T cells in the periphery. Although several studies have focused on the modulation of T cell function by the affinity of the TCR/pMHC interaction, the binding kinetics rules governing T cell activation remain poorly understood. Here we review recent data and propose a new model for the regulation of T cell function by TCR/pMHC binding kinetics.

Animals↗

PubMed2006

Virulent Salmonella enterica serovar typhimurium evades adaptive immunity by preventing dendritic cells from activating T cells.

Dendritic cells (DCs) constitute the link between innate and adaptive immunity by directly recognizing pathogen-associated molecular patterns (PAMPs) in bacteria and by presenting bacterial antigens to T cells. Recognition of PAMPs renders DCs as professional antigen-presenting cells able to prime naïve T cells and initiate adaptive immunity against bacteria. Therefore, interfering with DC function would promote bacterial survival and dissemination. Understanding the molecular mechanisms that have evolved in virulent bacteria to evade activation of adaptive immunity requires the characterization of virulence factors that interfere with DC function. Salmonella enterica serovar Typhimurium, the causative agent of typhoid-like disease in the mouse, can prevent antigen presentation to T cells by avoiding lysosomal degradation in DCs. Here, we show that this feature of virulent Salmonella applies in vivo to prevent activation of adaptive immunity. In addition, this attribute of virulent Salmonella requires functional expression of a type three secretion system (TTSS) and effector proteins encoded within the Salmonella pathogenicity island 2 (SPI-2). In contrast to wild-type virulent Salmonella, mutant strains carrying specific deletions of SPI-2 genes encoding TTSS components or effectors proteins are targeted to lysosomes and are no longer able to prevent DCs from activating T cells in vitro or in vivo. SPI-2 mutant strains are attenuated in vivo, showing reduced tissue colonization and enhanced T-cell activation, which confers protection against a challenge with wild-type virulent Salmonella. Our data suggest that impairment of DC function by the activity of SPI-2 gene products is crucial for Salmonella pathogenesis.

Animals↗

PubMed2005

T cell receptor binding kinetics required for T cell activation depend on the density of cognate ligand on the antigen-presenting cell.

CD8(+) T cells recognize peptides of eight to nine amino acid residues long in the context of MHC class I molecules on the surface of antigen-presenting cells (APCs). This recognition event is highly sensitive, as evidenced by the fact that T cells can be activated by cognate peptide/MHC complex (pMHC) at extremely low densities (1-50 molecules). High sensitivity is particularly valuable for detection of antigens at low density, such as those derived from tumor cells and intracellular pathogens, which can down-modulate cognate pMHCs from the surface of APCs to evade recognition by the adaptive immune system. T cell activation is only triggered in response to interactions between the T cell receptor (TCR) and the pMHC ligand that reach a specific half-life threshold. However, interactions with excessively long half-lives result in impaired T cell activation. Thus, efficient T cell activation by pMHC on the surface of APCs requires an optimal dwell time of TCR-pMHC interaction. Here, we show that, although this is a requirement at low cognate pMHC density on the APC surface, at high epitope density there is no impairment of T cell activation by extended TCR-pMHC dwell times. This observation was predicted by mathematical simulations for T cell activation by pMHC at different densities and supported by experiments performed on APCs selected for varied expression of cognate pMHC. According to these results, effective T cell activation depends on a complex interplay between inherent TCR-pMHC binding kinetics and the epitope density on the APC.

Antigen-Presenting Cells↗