Anergic T cells actively suppress T cell responses via the antigen-presenting cell

We here show that anergic T cells are active mediators of T cell suppression. In co-culture experiments, we found that anergic T cells, derived from established rat T cell clones and rendered anergic via T cell presentation of the specific antigen (Ag), were active inhibitors of T cell responses. Anergic T cells inhibited not only the responses of T cells with the same Ag specificity as the anergic T cells, but were also capable of efficiently inhibiting polyclonal T cell responses directed to other epitopes. This suppression required close cell-cell contact between antigen-presenting cells (APC), anergic T cells and responder T cells, and only occurred when the epitope recognized by the anergic T cell was present. The suppression was not caused by passive competition for ligands on the APC surface, IL-2 consumption, or cytolysis, and was not mediated by soluble factors derived from anergic T cells that were stimulated with their specific Ag. When responder T cells were added 24 h after co-culturing anergic cells in the presence of Ag and APC, T cell responses were still suppressed, indicating that the suppressive effect was persistently present. However, anergic T cells were not able to suppress responder T cells that had already received a full activation signal. We propose that suppression by anergic T cells is mediated via the APC, either through modulation of the T cell-activating capacity of the APC (APC/T cell interaction), or by inhibition of T cells recognizing their ligand in close proximity on the same APC (T/T cell interaction).     

Zinc finger protein GFI-1 has low oncogenic potential but cooperates strongly with pim and myc genes in T-cell lymphomagenesis

The gfi-1 gene encodes a zinc finger containing protein that is specifically expressed in T-lymphocytes and is a frequent target of proviral insertion in T-cell lymphoma provoked by infection with MoMuLV--a non acute transforming retrovirus. Expression of a gfi-1 transgene targeted to T-cells by the lck proximal promoter provokes a reduction of peripheral CD4 and CD8 positive T-cells but nevertheless weakly predisposes transgenic animals for the development of T-cell lymphoma. Forced coexpression of the serine/threonine kinase Pim-1 can partially restore normal T-cell numbers in double pim-1/gfi-1 transgenic mice. Moreover, the combinatorial expression of Pim-1 and Gfi-1 leads to accelerated development of T-cell lymphoma with a mean latency period of 114 days. A similar accelerated rate of lymphoma development was observed when lck-gfi-1 mice were crossed with mice that carry a L-myc gene targeted to be expressed at high levels in T-cells. The results show that gfi-1 can act with low activity as a dominant oncogene when overexpressed but also demonstrate that it is most efficient only in the presence of a cooperative partner protein as for example Pim-1 or L-Myc. In addition, the results suggest that Pim-1 and Gfi-1 are acting synergistically in both T-cell lymphomagenesis and T-cell development.     

An information-theoretic approach to combining object models

This paper introduces a new method for combining different object models. By determining a configuration of the models, which maximizes their mutual information, the proposed method creates a unified hypothesis from multiple object models on the fly without prior training. To validate the effectiveness of the proposed method, experiments are conducted in which human faces are detected and localized in images by combining different face models.     

The anomalous melting behavior of water in aqueous PVME solutions

The Wertheim lattice thermodynamic perturbation theory is used to predict the liquid-liquid and solid-liquid coexistence data for a model polymer solution. The theory predicts bimodal LCST phase behavior and an unusual step with composition in the solid-liquid equilibrium of the solvent.The theoretical solid-liquid equilibrium calculations are used to interpret experimental data obtained for aqueous solutions of poly(vinyl methyl ether) (PVME), which is known to show bimodal LCST phase behavior. An experimental method is proposed, employing Fourier transform infrared (FTIR) spectroscopy to determine the equilibrium melting line of water in the presence of PVME. In addition, the complete melting line of water is obtained by partial integration of the melting endotherm observed using modulated temperature differential scanning calorimetry (MTDSC). Both, the FTIR and MTDSC methods are in good agreement, experimentally confirming the predicted step with composition in the solid-liquid equilibrium. This peculiar concentration dependence of the melting curve of ice provides a new explanation for the inhibited crystallization of water in aqueous PVME solutions, since the actual supercooling (at high polymer concentration) is smaller than it could be anticipated for a conventional course of the melting curve. Hence, the vicinity of the glass transition region in these highly concentrated polymer mixtures leads to a dramatic slowing down of the nucleation rate and thus the subsequent crystallization. Moreover, the atypical shape of the equilibrium melting line also provides a new explanation for the double melting endotherm observed in (MT)DSC experiments, which is conventionally attributed to the melting at different temperatures of bound and free water.     

Activation of trehalase during growth induction by nitrogen sources in the yeast Saccharomyces cerevisiae depends on the free catalytic subunits of camp-dependent protein kinase,but not on functional ras proteins

Addition of a nitrogen-source to glucose-repressed, nitrogen-starved G0 cells of the yeast Saccharomyces cerevisiae in the presence of a fermentable carbon source induces growth and causes within a few minutes a five-fold, protein-synthesis-independent increase in the activity of trehalase. Nitrogen-activated trehalase could be deactivated in vitro by alkaline phosphatase treatment, supporting the idea that the activation is triggered by phosphorylation. Yeast strains containing only one of the three TPK genes (which encode the catalytic subunit of cAMP-dependent protein kinase) showed different degrees of nitrogen-induced trehalase activation. The order of effectiveness was different from that previously reported for glucose-induced activation of trehalase in glucose-derepressed yeast cells. Further reduction of TPK-encoded catalytic subunit activity by partially inactivating point mutations in the remaining TPK gene further diminished nitrogen-induced trehalase activation, while deletion of the BCY1 gene (which encodes the regulatory subunit) in the same strains resulted in an increase in the extent of activation. Deletion of the RAS genes in such a tpk^w1 bcy1 strain had no effect. These results are consistent with mediation of nitrogen-induced trehalase activation by the free catalytic subunits alone. They support our previous conclusion that cAMP does not act as second messenger in this nitrogen-induced activation process and our suggestion that a novel nitrogen-induced signaling pathway integrates with the cAMP pathway at the level of the free catalytic subunits of protein kinase A. Western blot experiments showed that the differences in the extent of trehalase activation were not due to differences in trehalase expression. On the other hand, we cannot completely exclude that protein kinase A influences the nitrogen-induced activation mechanism itself rather than acting directly on trehalase. However, any such alternative explanation requires the existence of an additional, yet unknown, mechanism for activation of trehalase besides the well-established regulation by protein kinase A.     

On Discriminative Bayesian Network Classifiers and Logistic Regression

Discriminative learning of the parameters in the naive Bayes model is known to be equivalent to a logistic regression problem. Here we show that the same fact holds for much more general Bayesian network models, as long as the corresponding network structure satisfies a certain graph-theoretic property. The property holds for naive Bayes but also for more complex structures such as tree-augmented naive Bayes (TAN) as well as for mixed diagnostic-discriminative structures. Our results imply that for networks satisfying our property, the conditional likelihood cannot have local maxima so that the global maximum can be found by simple local optimization methods. We also show that if this property does not hold, then in general the conditional likelihood can have local, non-global maxima. We illustrate our theoretical results by empirical experiments with local optimization in a conditional naive Bayes model. Furthermore, we provide a heuristic strategy for pruning the number of parameters and relevant features in such models. For many data sets, we obtain good results with heavily pruned submodels containing many fewer parameters than the original naive Bayes model.Editors: Pedro Larrañaga, Jose A. Lozano, Jose M. Peña and Iñaki Inza