Anchor Side Chains of Short Peptide Fragments Trigger Ligand-Exchange of Class II MHC Molecules

Class II MHC molecules display peptides on the cell surface for the surveillance by CD4+ T cells. To ensure that these ligands accurately reflect the content of the intracellular MHC loading compartment, a complex processing pathway has evolved that delivers only stable peptide/MHC complexes to the surface. As additional safeguard, MHC molecules quickly acquire a ‘non-receptive’ state once they have lost their ligand. Here we show now that amino acid side chains of short peptides can bypass these safety mechanisms by triggering the reversible ligand-exchange. The catalytic activity of dipeptides such as Tyr-Arg was stereo-specific and could be enhanced by modifications addressing the conserved H-bond network near the P1 pocket of the MHC molecule. It affected both antigen-loading and ligand-release and strictly correlated with reported anchor preferences of P1, the specific target site for the catalytic side chain of the dipeptide. The effect was evident also in CD4+ T cell assays, where the allele-selective influence of the dipeptides translated into increased sensitivities of the antigen-specific immune response. Molecular dynamic calculations support the hypothesis that occupation of P1 prevents the ‘closure’ of the empty peptide binding site into the non-receptive state. During antigen-processing and -presentation P1 may therefore function as important “sensor” for peptide-load. While it regulates maturation and trafficking of the complex, on the cell surface, short protein fragments present in blood or lymph could utilize this mechanism to alter the ligand composition on antigen presenting cells in a catalytic way

Enhancement of Tumour-Specific Immune Responses In Vivo by ‘MHC Loading-Enhancer’ (MLE)

BACKGROUND:Class II MHC molecules (MHC II) are cell surface receptors displaying short protein fragments for the surveillance by CD4+ T cells. Antigens therefore have to be loaded onto this receptor in order to induce productive immune responses. On the cell surface, most MHC II molecules are either occupied by ligands or their binding cleft has been blocked by the acquisition of a non-receptive state. Direct loading with antigens, as required during peptide vaccinations, is therefore hindered. PRINCIPAL FINDINGS:Here we show, that the in vivo response of CD4+ T cells can be improved, when the antigens are administered together with 'MHC-loading enhancer' (MLE). MLE are small catalytic compounds able to open up the MHC binding site by triggering ligand-release and stabilizing the receptive state. Their enhancing effect on the immune response was demonstrated here with an antigen from the influenza virus and tumour associated antigens (TAA) derived from the NY-ESO-1 protein. The application of these antigens in combination with adamantane ethanol (AdEtOH), an MLE compound active on human HLA-DR molecules, significantly increased the frequency of antigen-specific CD4+ T cells in mice transgenic for the human MHC II molecule. Notably, the effect was evident only with the MLE-susceptible HLA-DR molecule and not with murine MHC II molecules non-susceptible for the catalytic effect of the MLE. CONCLUSION:MLE can specifically increase the potency of a vaccine by facilitating the efficient transfer of the antigen onto the MHC molecule. They may therefore open a new way to improve vaccination efficacy and tumour-immunotherapy

Rational exaggeration and counter-exaggeration in information aggregation games

We study an information aggregation game in which each of a finite collection of “senders” receives a private signal and submits a report to the center, who then makes a decision based on the average of these reports. The integration of three features distinguishes our framework from the related literature: players’ reports are aggregated by a mechanistic averaging rule, their strategy sets are intervals rather than binary choices, and they are ex ante heterogeneous. In this setting, players engage in a “tug-of-war,” as they exaggerate and counter-exaggerate in order to manipulate the center’s decision. While incentives to exaggerate have been studied extensively, the phenomenon of counter-exaggeration is less well understood. Our main results are as follows. First, the cycle of counter-exaggeration can be broken only by the imposition of exogenous bounds on the space of admissible sender reports. Second, in the unique pure-strategy equilibrium, all but at most one player is constrained with positive probability by one of the report bounds. Our third and fourth results hold for a class of “anchored” games. We show that if the report space is strictly contained in the signal space, then welfare is increasing in the size of the report space, but if the containment relation is reversed, welfare is independent of the size of the space. Finally, the equilibrium performance of our heterogeneous players can be unambiguously ranked: a player’s equilibrium payoff is inversely related to the probability that her exaggeration will be thwarted by the report bounds

Combined group and individual schema therapy for borderline personality disorder: a pilot study

Background and Objectives: Schema Therapy (ST) is a highly effective treatment for Borderline Personality Disorder (BPD). In a group format, delivery costs could be reduced and recovery processes catalyzed by specific use of group processes. As patients may also need individual attention, we piloted the combination of individual and group-ST. Methods: Two cohorts of BPD patients (N = 8, N = 10) received a combination of weekly group-ST and individual ST for 2 years, with 6 months extra individual ST if indicated. Therapists were experienced in individual ST but not in group-ST. The second cohort of therapists was trained in group-ST by specialists. This made it possible to explore the training effects. Assessments of BPD manifestations and secondary measures took place every 6 months up to 2.5 years. Change over time and differences between cohorts were analyzed with mixed regression. Results: Dropout from treatment was 33.3% in Year 1, and 5.6% in Year 2, without cohort differences. BPD manifestations reduced significantly, with large effect sizes, and 77% recovery at 30 months. Large improvements were also found on general psychopathological symptoms, schema (mode) measures, quality of life, and happiness. Cohort-2 tended to improve faster, but there were no differences between cohorts in the long term. Limitations: The study was uncontrolled, training effects might have been non-specific, and the sample size was relatively small. Conclusions: Combined group-individual ST can be an effective treatment, but dropout might be higher than from individual ST. Addition of specialized group-ST seems to speed up recovery compared to only individual ST