Lysosomes in T Cell Immunity and Aging

Lysosomes were initially recognized as degradation centers that regulate digestion and recycling of cellular waste. More recent studies document that the lysosome is an important signaling hub that regulates cell metabolism. Our knowledge of the role of lysosomes in immunity is mostly derived from innate immune cells, especially lysosomal degradation-specialized cells such as macrophages and dendritic cells. Their function in adaptive immunity is less understood. However, with the recent emphasis on metabolic regulation of T cell differentiation, lysosomes are entering center stage in T cell immunology. In this review, we will focus on the role of lysosomes in adaptive immunity and discuss recent findings on lysosomal regulation of T cell immune responses and lysosomal dysfunction in T cell aging.

TCRdb: a comprehensive database for T-cell receptor sequences with powerful search function

T cells and the T-cell receptor (TCR) repertoire play pivotal roles in immune response and immunotherapy. TCR sequencing (TCR-Seq) technology has enabled accurate profiling TCR repertoire and currently a large number of TCR-Seq data are available in public. Based on the urgent need to effectively re-use these data, we developed TCRdb, a comprehensive human TCR sequences database, by a uniform pipeline to characterize TCR sequences on TCR-Seq data. TCRdb contains more than 277 million highly reliable TCR sequences from over 8265 TCR-Seq samples across hundreds of tissues/clinical conditions/cell types. The unique features of TCRdb include: (i) comprehensive and reliable sequences for TCR repertoire in different samples generated by a strict and uniform pipeline of TCRdb; (ii) powerful search function, allowing users to identify their interested TCR sequences in different conditions; (iii) categorized sample metadata, enabling comparison of TCRs in different sample types; (iv) interactive data visualization charts, describing the TCR repertoire in TCR diversity, length distribution and V-J gene utilization. The TCRdb database is freely available at http://bioinfo.life.hust.edu.cn/TCRdb/ and will be a useful resource in the research and application community of T cell immunology.

Crystal structure of the giant panda MHC class I complex: first insights into the viral peptide presentation profile in the bear family

ABSTRACTThe viral cytotoxic T lymphocyte (CTL) epitope peptides presented by classical MHC-I molecules require the assembly of a peptide-MHC-I-β2m (aka pMHC-I) trimolecular complex for TCR recognition, which is the critical activation link for triggering antiviral T cell immunity. Ursidae includes 5 genera and 8 species; however, research on T cell immunology in this family, especially structural immunology, is lacking. In this study, the structure of the key trimolecular complex pMHC-1 (aka pAime-128), which binds a peptide from canine distemper virus, was solved for the first time using giant panda as a representative species of Ursidae. The structural characteristics of the giant panda pMHC-I complex, including the unique pockets in the peptide-binding groove (PBG), were analyzed in detail. Comparing the panda pMHC-I to others in the bear family and extending the comparison to other mammals revealed distinct features. The interaction between MHC-I and β2m, the features of pAime-128 involved in TCR docking and CD8 binding, the anchor sites in the PBG, and the CTL epitopes of potential viruses that infect pandas were concretely clarified. Unique features of pMHC-I viral antigen presentation in the panda were revealed by solving the three-dimensional structure of pAime-128. The distinct characteristics of pAime-128 indicate an unusual event that emerged during the evolution of the MHC system in the bear family. These results provide a new platform for research on panda CTL immunity and the design of vaccines for application in the bear family.IMPORTANCEUrsidae includes 5 genera and 8 species; however, the study of its immunology, especially structural immunology, is extremely rare to date. In this paper, we first crystallized the key complex pMHC-I, taking the giant panda as its representative species. Structural characteristics of the giant panda pMHC-I complexes, contains the unique pockets of PBG were analyzed in detail. Comparison of the panda pMHC-I in the bear family and other mammals, almost definite features was displayed. Meanwhile, the interaction between HC and LV, the unique features of pMHC-I in the CD8 binding and TCR docking, validation of anchor site in the PBG, and epitopes of potential viruses infected with the pandas, were concretely clarified. These unique characteristics of pMHC-I clearly indicate an unusual situation during the evolution of MHC molecules in the endangered pandas. These results also provide a novel platform for further study of panda T cell immunology and vaccines.

An ultrasensitive T-cell receptor detection method for TCR-Seq and RNA-Seq data

T-cell receptors (TCRs) recognizing antigens play vital roles in T-cell immunology. Surveying TCR repertoires by characterizing complementarity-determining region 3 (CDR3) can provide valuable insights into the immune community underlying pathologic conditions, which will benefit neoantigen discovery and cancer immunotherapy. Here we present a novel tool named CATT, which can apply on TCR sequencing (TCR-Seq), RNA-Seq, and single-cell TCR(RNA)-Seq data to characterize CDR3 repertoires. CATT integrated maximum-network-flow based micro-assembly algorithm, data-driven error correction model, and Bayes classification algorithm, to self-adaptively and ultra-sensitively characterize CDR3 repertoires with high accuracy. Benchmark results of datasets from in silico and real conditions demonstrated that CATT showed superior recall and precision compared with other prevalent tools, especially for datasets with short read length and small data size. By applying CATT on a TCR-Seq dataset from aplastic anemia patients, we found the skewing of TCR repertoire was due to the oligoclonal expansion of effector memory T-cells. CATT will be a powerful tool for researchers conducting TCR and immune repertoire studies. CATT is freely available at http://bioinfo.life.hust.edu.cn/CATT.

Moving target: shifting the focus to pulmonary sarcoidosis as an autoimmune spectrum disorder

Despite more than a century of research, the causative agent(s) in sarcoidosis, a heterogeneous granulomatous disorder mainly affecting the lungs, remain(s) elusive. Following identification of genetic factors underlying different clinical phenotypes, increased understanding of CD4+ T-cell immunology, which is believed to be central to sarcoid pathogenesis, as well as the role of B-cells and other cells bridging innate and adaptive immunity, contributes to novel insights into the mechanistic pathways influencing disease resolution or chronicity. Hopefully, new perspectives and state-of-the-art technology will help to shed light on the still-elusive enigma of sarcoid aetiology. This perspective article highlights a number of recent advances in the search for antigenic targets in sarcoidosis, as well as the main arguments for sarcoidosis as a spectrum of autoimmune conditions, either as a result of an external (microbial) trigger and/or due to defective control mechanisms regulating the balance between T-cell activation and inhibition.