CD4+ T cells have a major role in regulating immune responses. They are activated by recognition of peptides mostly generated from exogenous antigens through the major histocompatibility complex (MHC) class II pathway. Identification of epitopes is important and computational prediction of epitopes is used widely to save time and resources. Although there are algorithms to predict binding affinity of peptides to MHC II molecules, no accurate methods exist to predict which ligands are generated as a result of natural antigen processing. We utilized a dataset of around 14,000 naturally processed ligands identified by mass spectrometry of peptides eluted from MHC class II expressing cells to investigate the existence of sequence signatures potentially related to the cleavage mechanisms that liberate the presented peptides from their source antigens. This analysis revealed preferred amino acids surrounding both N- and C-terminuses of ligands, indicating sequence-specific cleavage preferences. We used these cleavage motifs to develop a method for predicting naturally processed MHC II ligands, and validated that it had predictive power to identify ligands from independent studies. We further confirmed that prediction of ligands based on cleavage motifs could be combined with predictions of MHC binding, and that the combined prediction had superior performance. However, when attempting to predict CD4+ T cell epitopes, either alone or in combination with MHC binding predictions, predictions based on the cleavage motifs did not show predictive power. Given that peptides identified as epitopes based on CD4+ T cell reactivity typically do not have well-defined termini, it is possible that motifs are present but outside of the mapped epitope. Our attempts to take that into account computationally did not show any sign of an increased presence of cleavage motifs around well-characterized CD4+ T cell epitopes. While it is possible that our attempts to translate the cleavage motifs in MHC II ligand elution data into T cell epitope predictions were suboptimal, other possible explanations are that the cleavage signal is too diluted to be detected, or that elution data are enriched for ligands generated through an antigen processing and presentation pathway that is less frequently utilized for T cell epitopes.

BackgroundPrediction of T cell immunogenicity is a topic of considerable interest, both in terms of basic understanding of the mechanisms of T cells responses and in terms of practical applications. HLA binding affinity is often used to predict T cell epitopes, since HLA binding affinity is a key requisite for human T cell immunogenicity. However, immunogenicity at the population it is complicated by the high level of variability of HLA molecules, potential other factors beyond HLA as well as the frequent lack of HLA typing data. To overcome those issues, we explored an alternative approach to identify the common characteristics able to distinguish immunogenic peptides from non-recognized peptides.MethodsSets of dominant epitopes derived from peer-reviewed published papers were used in conjunction with negative peptides from the same experiments/donors to train neural networks and generate an “immunogenicity score.” We also compared the performance of the immunogenicity score with previously described method for immunogenicity prediction based on HLA class II binding at the population level.ResultsThe immunogenicity score was validated on a series of independent datasets derived from the published literature, representing 57 independent studies where immunogenicity in human populations was assessed by testing overlapping peptides spanning different antigens. Overall, these testing datasets corresponded to over 2,000 peptides and tested in over 1,600 different human donors. The 7-allele method prediction and the immunogenicity score were associated with similar performance [average area under the ROC curve (AUC) values of 0.703 and 0.702, respectively] while the combined methods reached an average AUC of 0.725. This increase in average AUC value is significant compared with the immunogenicity score (p = 0.0135) and a strong trend toward significance is observed when compared to the 7-allele method (p = 0.0938). The new immunogenicity score method is now freely available using CD4 T cell immunogenicity prediction tool on the Immune Epitope Database website ().ConclusionThe new immunogenicity score predicts CD4 T cell immunogenicity at the population level starting from protein sequences and with no need for HLA typing. Its efficacy has been validated in the context of different antigen sources, ethnicities, and disparate techniques for epitope identification.

It has been observed that countries that implemented new public management (NPM) reforms are currently witnessing growing complaints about a decline in the policy capacity of their public services. Australia is a part of this trend with public sector leaders increasingly voicing concern about policy capacity decline within the Australian Public Service (APS). This article sets out to examine whether there is an empirical basis for this discourse and to assess allegations that NPM reforms have contributed to any related shifts. It draws on rail policy and the Department of Transport as its case study. It finds that the reforms transformed role of the department in a way that enhanced strategic policy capacity. However, the reforms also introduced a number of structural impediments that make it difficult for the new role to be effectively executed.

Policy innovation is a significant challenge for the public sector. This article illustrates its magnitude through a case study of the National Innovation Summit. The article concludes that the Summit represented an elaborate process of search and engagement that sanctioned an outcome that was, in most respects, largely pre-determined. Its outreach and deliberations served the political purpose of mobilising industry and media attention and communicating the government's commitment. But there is no evidence that it exercised any substantive influence on policy development. The obstacles confounding any other outcome are considerable. Strategic thinking is inhibited by various organisational factors including lock-in to a present successful strategy, the constraints on policy choices associated with multiple veto points and the need to maintain medium term fiscal and policy discipline across a wide range of agencies and claimants. The article explores ways these inhibitions might be overcome.

This fascinating book reflects on how economics has become central to our lives, and how the 'economic rationalist' perspective has become the lens through which all matters in Australian public life are viewed. It explains how this economic worldview systematically overlooks important social issues and how it transforms Australian culture. How to Argue with an Economist invites a broad general audience into debates that were once reserved for experts. Lindy Edwards, a former economic adviser in the Prime Minister's Department, has a talent for expressing concepts simply. She distils economics' key ideas into a lively and enjoyable read, explaining how economists think and then how you can argue with them.