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Killer cell immunoglobulin-like receptors (KIRs) influence both innate and adaptive immunity. But while the role of KIRs in NK-mediated innate immunity is well-documented, the impact of KIRs on the T cell response in human disease is not known. Here we test the hypothesis that an individual's KIR genotype affects the efficiency of their HLA class I-mediated antiviral immune response and the outcome of viral infection. We show that, in two unrelated viral infections, hepatitis C virus and human T lymphotropic virus type 1, possession of the KIR2DL2 gene enhanced both protective and detrimental HLA class I- restricted anti-viral immunity. These results reveal a novel role for inhibitory KIRs. We conclude that inhibitory KIRs, in synergy with T cells, are a major determinant of the outcome of persistent viral infection. [ABSTRACT FROM AUTHOR]

Theoretical methods for predicting CD8+ T-cell epitopes are an important tool in vaccine design and for enhancing our understanding of the cellular immune system. The most popular methods currently available produce binding affinity predictions across a range of MHC molecules. In comparing results between these MHC molecules, it is common practice to apply a normalization procedure known as rescaling, to correct for possible discrepancies between the allelic predictors. Using two of the most popular prediction software packages, NetCTL and NetMHC, we tested the hypothesis that rescaling removes genuine biological variation from the predicted affinities when comparing predictions across a number of MHC molecules. We found that removing the condition of rescaling improved the prediction software's performance both qualitatively, in terms of ranking epitopes, and quantitatively, in the accuracy of their binding affinity predictions. We suggest that there is biologically significant variation among class 1 MHC molecules and find that retention of this variation leads to significantly more accurate epitope prediction. [ABSTRACT FROM AUTHOR]

The solute carrier transporter family 6 (SLC6) is of key interest for their critical role in the transport of small amino acids or amino acid-like molecules. Their dysfunction is strongly associated with human diseases such as including schizophrenia, depression, and Parkinson's disease. Linking single point mutations to disease may support insights into the structure-function relationship of these transporters. This work aimed to develop a computational model for predicting the potential pathogenic effect of single point mutations in the SLC6 family. Missense mutation data was retrieved from UniProt, LitVar, and ClinVar, covering multiple protein-coding transcripts. As encoding approach, amino acid descriptors were used to calculate the average sequence properties for both original and mutated sequences. In addition to the full-sequence calculation, the sequences were cut into twelve domains. The domains are defined according to the transmembrane domains of the SLC6 transporters to analyse the regions' contributions to the pathogenicity prediction. Subsequently, several classification models, namely Support Vector Machine (SVM), Logistic Regression (LR), Random Forest (RF), and Extreme Gradient Boosting (XGBoost) with the hyperparameters optimized through grid search were built. For estimation of model performance, repeated stratified k-fold cross-validation was used. The accuracy values of the generated models are in the range of 0.72 to 0.80. Analysis of feature importance indicates that mutations in distinct regions of SLC6 transporters are associated with an increased risk for pathogenicity. When applying the model on an independent validation set, the performance in accuracy dropped to averagely 0.6 with high precision but low sensitivity scores., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Down-regulation of receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR) is achieved by endocytosis of the receptor followed by degradation or recycling. We demonstrated that in the absence of ligand, increased phosphatidylinositol 3,4,5-trisphosphate (PIP3) concentrations induced clathrin- and dynamin-mediated endocytosis of EGFR but not that of transferrin or G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors. Endocytosis of the receptor in response to binding of EGF resulted in a decrease in the abundance of the EGFR, but PIP3-induced internalization decreased receptor ubiquitination and phosphorylation and resulted in recycling of the receptor to the plasma membrane. An RNA interference (RNAi) screen directed against lipid-binding domain-containing proteins identified polarity complex proteins, including PARD3 (partitioning defective 3), as essential for PIP3-induced receptor tyrosine kinase recycling. Thus, PIP3 and polarity complex proteins regulate receptor tyrosine kinase trafficking, which may enhance cellular responsiveness to growth factors.

In the last 30 years, many of the mechanisms behind signal transduction, the process by which the cell takes extracellular signals as an input and converts them to a specific cellular phenotype, have been experimentally determined. With these discoveries, however, has come the realization that the architecture of signal transduction, the signaling network, is incredibly complex. Although the main pathways between receptor and output are well-known, there is a complex net of regulatory features that include crosstalk between different pathways, spatial and temporal effects, and positive and negative feedbacks. Hence, modeling approaches have been used to try and unravel some of these complexities. We use the mitogen-activated protein kinase cascade to illustrate chemical kinetic and logic approaches to modeling signaling networks. By using a common well-known model, we illustrate here the assumptions and level of detail behind each modeling approach, which serves as an introduction to the more detailed discussions of each in the accompanying chapters in this book.

While most carriers of human T-cell leukemia virus type 1 (HTLV-1) remain asymptomatic throughout their lifetime, infection is associated with the development of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The exact parameters that determine these outcomes are unknown but are believed to include host genetic factors that control the immune response to infection. Host response to fellow retroviridae member HIV is influenced by the expression of members of the Killer Immunoglobulin Receptor (KIR) family including KIR3DS1. In this study we examined the association of KIR3DS1 with the outcome of HTLV-1 infection in three geographically distinct cohorts (Jamaican, Japanese and Brazilian). Despite increased prevalence of KIR3DS1 in the HAM/TSP patients of the Jamaican cohort, we found no evidence for a role of KIR3DS1 in influencing control of proviral load or disease outcome. This suggests that unlike HIV, KIR3DS1-mediated regulation of HTLV-1 infection does not occur, or is ineffective., (Published by Elsevier Inc.)

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic and progressive disorder caused by the human T-lymphotropic virus type 1 (HTLV-1). In HTLV-1 infection, a strong cytotoxic T cell (CTL) response is mounted against the immunodominant protein Tax. Previous studies carried out by our group reported that increased IFN-γ enzyme-linked immunospot (ELISPOT) responses against the region spanning amino acids 161 to 233 of the Tax protein were associated with HAM/TSP and increased HTLV-1 proviral load (PVL). An exploratory study was conducted on 16 subjects with HAM/TSP, 13 asymptomatic carriers (AC), and 10 HTLV-1-seronegative controls (SC) to map the HAM/TSP-associated CTL epitopes within Tax region 161-233. The PVL of the infected subjects was determined and the specific CTL response was evaluated with a 6-h incubation IFN-γ ELISPOT assay using peripheral blood mononuclear cells (PBMCs) stimulated with 16 individual overlapping peptides covering the Tax region 161-233. Other proinflammatory and Th1/Th2 cytokines were also quantified in the supernatants by a flow cytometry multiplex assay. In addition, a set of human leukocyte antigen (HLA) class I alleles that bind with high affinity to the CTL epitopes of interest was determined using computational tools. Univariate analyses identified an association between ELISPOT responses to two new CTL epitopes, Tax 173-185 and Tax 181-193, and the presence of HAM/TSP as well as an increased PVL. The HLA-A*6801 allele, which is predicted to bind to the Tax 181-193 peptide, was overpresented in the HAM/TSP patients tested.