RESUMO
Cellular immunity relies on the ability of a T-cell receptor (TCR) to recognize a peptide (p) presented by a class I major histocompatibility complex (MHC) receptor on the surface of a cell. The TCR-peptide-MHC (TCRpMHC) interaction is a crucial step in activating T-cells, and the structural characteristics of these molecules play a significant role in determining the specificity and affinity of this interaction. Hence, obtaining 3D structures of TCRpMHC complexes offers valuable insights into various aspects of cellular immunity and can facilitate the development of T-cell-based immunotherapies. Here, we aimed to compare three popular web servers for modeling the structures of TCRpMHC complexes, namely ImmuneScape (IS), TCRpMHCmodels, and TCRmodel2, to examine their strengths and limitations. Each method employs a different modeling strategy, including docking, homology modeling, and deep learning. The accuracy of each method was evaluated by reproducing the 3D structures of a dataset of 87 TCRpMHC complexes with experimentally determined crystal structures available on the Protein Data Bank (PDB). All selected structures were limited to human MHC alleles, presenting a diverse set of peptide ligands. A detailed analysis of produced models was conducted using multiple metrics, including Root Mean Square Deviation (RMSD) and standardized assessments from CAPRI and DockQ. Special attention was given to the complementarity-determining region (CDR) loops of the TCRs and to the peptide ligands, which define most of the unique features and specificity of a given TCRpMHC interaction. Our study provides an optimistic view of the current state-of-the-art for TCRpMHC modeling but highlights some remaining challenges that must be addressed in order to support the future application of these tools for TCR engineering and computer-aided design of TCR-based immunotherapies.
RESUMO
The blood brain barrier (BBB) forms a stringent barrier that protects the brain from components in the circulation that could interfere with neuronal function. At the same time, the BBB enables selective transport of critical nutrients and other chemicals to the brain. Beyond these functions, another recently recognized function is even less characterized, specifically the role of the BBB in modulating behavior by affecting neuronal function in a sex-dependent manner. Notably, signaling in the adult Drosophila BBB is required for normal male courtship behavior. Courtship regulation also relies on male-specific molecules in the BBB. Our previous studies have demonstrated that adult feminization of these cells in males significantly lowered courtship. Here, we conducted microarray analysis of BBB cells isolated from males and females. Findings revealed that these cells contain male- and female-enriched transcripts, respectively. Among these transcripts, nuclear receptor Hr46/Hr3 was identified as a male-enriched BBB transcript. Hr46/Hr3 is best known for its essential roles in the ecdysone response during development and metamorphosis. In this study, we demonstrate that Hr46/Hr3 is specifically required in the BBB cells for courtship behavior in mature males. The protein is localized in the nuclei of sub-perineurial glial cells (SPG), indicating that it might act as a transcriptional regulator. These data provide a catalogue of sexually dimorphic BBB transcripts and demonstrate a physiological adult role for the nuclear receptor Hr46/Hr3 in the regulation of male courtship, a novel function that is independent of its developmental role.