-
Nucleic Acids Research Jul 2020Major histocompatibility complex (MHC) molecules are expressed on the cell surface, where they present peptides to T cells, which gives them a key role in the...
Major histocompatibility complex (MHC) molecules are expressed on the cell surface, where they present peptides to T cells, which gives them a key role in the development of T-cell immune responses. MHC molecules come in two main variants: MHC Class I (MHC-I) and MHC Class II (MHC-II). MHC-I predominantly present peptides derived from intracellular proteins, whereas MHC-II predominantly presents peptides from extracellular proteins. In both cases, the binding between MHC and antigenic peptides is the most selective step in the antigen presentation pathway. Therefore, the prediction of peptide binding to MHC is a powerful utility to predict the possible specificity of a T-cell immune response. Commonly MHC binding prediction tools are trained on binding affinity or mass spectrometry-eluted ligands. Recent studies have however demonstrated how the integration of both data types can boost predictive performances. Inspired by this, we here present NetMHCpan-4.1 and NetMHCIIpan-4.0, two web servers created to predict binding between peptides and MHC-I and MHC-II, respectively. Both methods exploit tailored machine learning strategies to integrate different training data types, resulting in state-of-the-art performance and outperforming their competitors. The servers are available at http://www.cbs.dtu.dk/services/NetMHCpan-4.1/ and http://www.cbs.dtu.dk/services/NetMHCIIpan-4.0/.
Topics: Amino Acid Motifs; Antigen Presentation; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Ligands; Machine Learning; Peptides; Software
PubMed: 32406916
DOI: 10.1093/nar/gkaa379 -
Cell Oct 2023The CD1 system binds lipid antigens for display to T cells. Here, we solved lipidomes for the four human CD1 antigen-presenting molecules, providing a map of self-lipid...
The CD1 system binds lipid antigens for display to T cells. Here, we solved lipidomes for the four human CD1 antigen-presenting molecules, providing a map of self-lipid display. Answering a basic question, the detection of >2,000 CD1-lipid complexes demonstrates broad presentation of self-sphingolipids and phospholipids. Whereas peptide antigens are chemically processed, many lipids are presented in an unaltered form. However, each type of CD1 protein differentially edits the self-lipidome to show distinct capture motifs based on lipid length and chemical composition, suggesting general antigen display mechanisms. For CD1a and CD1d, lipid size matches the CD1 cleft volume. CD1c cleft size is more variable, and CD1b is the outlier, where ligands and clefts show an extreme size mismatch that is explained by uniformly seating two small lipids in one cleft. Furthermore, the list of compounds that comprise the integrated CD1 lipidome supports the ongoing discovery of lipid blockers and antigens for T cells.
Topics: Humans; Antigen Presentation; Antigens, CD1; Lipidomics; Lipids; T-Lymphocytes; Amino Acid Motifs
PubMed: 37725977
DOI: 10.1016/j.cell.2023.08.022 -
Immunity Oct 2019Increasing evidence indicates CD4 T cells can recognize cancer-specific antigens and control tumor growth. However, it remains difficult to predict the antigens that...
Increasing evidence indicates CD4 T cells can recognize cancer-specific antigens and control tumor growth. However, it remains difficult to predict the antigens that will be presented by human leukocyte antigen class II molecules (HLA-II), hindering efforts to optimally target them therapeutically. Obstacles include inaccurate peptide-binding prediction and unsolved complexities of the HLA-II pathway. To address these challenges, we developed an improved technology for discovering HLA-II binding motifs and conducted a comprehensive analysis of tumor ligandomes to learn processing rules relevant in the tumor microenvironment. We profiled >40 HLA-II alleles and showed that binding motifs were highly sensitive to HLA-DM, a peptide-loading chaperone. We also revealed that intratumoral HLA-II presentation was dominated by professional antigen-presenting cells (APCs) rather than cancer cells. Integrating these observations, we developed algorithms that accurately predicted APC ligandomes, including peptides from phagocytosed cancer cells. These tools and biological insights will enable improved HLA-II-directed cancer therapies.
Topics: Algorithms; Alleles; Antigen Presentation; Antigen-Presenting Cells; Antigens, Neoplasm; CD4-Positive T-Lymphocytes; Cancer Vaccines; Datasets as Topic; Epitope Mapping; HLA Antigens; HLA-D Antigens; Histocompatibility Antigens Class II; Humans; Immunotherapy; Mass Spectrometry; Neoplasms; Protein Binding; Protein Interaction Domains and Motifs; Software
PubMed: 31495665
DOI: 10.1016/j.immuni.2019.08.012 -
Biomedicine & Pharmacotherapy =... May 2023Antibody Drug Conjugate (ADC) is an emerging technology to overcome the limitations of chemotherapy by selectively targeting the cancer cells. ADC binds with an antigen,... (Review)
Review
Antibody Drug Conjugate (ADC) is an emerging technology to overcome the limitations of chemotherapy by selectively targeting the cancer cells. ADC binds with an antigen, specifically over expressed on the surface of cancer cells, results decrease in bystander effect and increase in therapeutic index. The potency of an ideal ADC is entirely depending on several physicochemical factors such as site of conjugation, molecular weight, linker length, Steric hinderance, half-life, conjugation method, binding energy and so on. Inspite of the fact that there is more than 100 of ADCs are in clinical trial only 14 ADCs are approved by FDA for clinical use. However, to design an ideal ADC is still challenging and there is much more to be done. Here in this review, we have discussed the key components along with their significant role or contribution towards the efficacy of an ADC. Moreover, we also explained about the recent advancement in the conjugation method. Additionally, we spotlit the mode of action of an ADC, recent challenges, and future perspective regarding ADC. The profound knowledge regarding key components and their properties will help in the synthesis or production of different engineered ADCs. Therefore, contributes to develop an ADC with low safety concern and high therapeutic index. We hope this review will improve the understanding and encourage the practicing of research in anticancer ADCs development.
Topics: Immunoconjugates; Antigens; Antineoplastic Agents
PubMed: 36841027
DOI: 10.1016/j.biopha.2023.114408 -
Nature Immunology May 2022LAG3 is an inhibitory receptor that is highly expressed on exhausted T cells. Although LAG3-targeting immunotherapeutics are currently in clinical trials, how LAG3...
LAG3 is an inhibitory receptor that is highly expressed on exhausted T cells. Although LAG3-targeting immunotherapeutics are currently in clinical trials, how LAG3 inhibits T cell function remains unclear. Here, we show that LAG3 moved to the immunological synapse and associated with the T cell receptor (TCR)-CD3 complex in CD4 and CD8 T cells, in the absence of binding to major histocompatibility complex class II-its canonical ligand. Mechanistically, a phylogenetically conserved, acidic, tandem glutamic acid-proline repeat in the LAG3 cytoplasmic tail lowered the pH at the immune synapse and caused dissociation of the tyrosine kinase Lck from the CD4 or CD8 co-receptor, which resulted in a loss of co-receptor-TCR signaling and limited T cell activation. These observations indicated that LAG3 functioned as a signal disruptor in a major histocompatibility complex class II-independent manner, and provide insight into the mechanism of action of LAG3-targeting immunotherapies.
Topics: Antigens, CD; CD3 Complex; CD8 Antigens; CD8-Positive T-Lymphocytes; Histocompatibility Antigens Class II; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Receptors, Antigen, T-Cell; Signal Transduction; Lymphocyte Activation Gene 3 Protein
PubMed: 35437325
DOI: 10.1038/s41590-022-01176-4 -
Theranostics 2020Given that heterogeneous expression and variants of antigens on solid tumors are responsible for relapse after chimeric antigen receptor (CAR)-T cell therapy, we...
Given that heterogeneous expression and variants of antigens on solid tumors are responsible for relapse after chimeric antigen receptor (CAR)-T cell therapy, we hypothesized that combinatorial targeting two tumor-associated antigens would lessen this problem and enhance the antitumor activity of T cells. The co-expression level of CD70 and B7-H3 was analyzed in multiple tumor tissue samples. Further, two putative antigens were identified in The Cancer Genome Atlas and Gene Expression Profiling Interactive Analysis database. Two CD70 targeted CARs with different antigen binding domain, truncated CD27 and CD70 specific single-chain antibody fragment (scFv), were designed to screen a more suitable target-antigen binding moiety. Accordingly, we designed a bivalent tandem CAR (TanCAR) and further assessed the anti-tumor efficacy of TanCAR-T cells and . Our results indicated that co-expression of CD70 and B7-H3 was observed on multiple tumor types including kidney, breast, esophageal, liver, colon cancer, glioma as well as melanoma. The CD70 targeted CAR-T cells with binding moiety of CD70 specific scFv exhibit a higher affinity and antitumor effect against CD70 tumor cells. TanCAR-T cells induced enhanced ability of cytolysis and cytokine release over unispecific CAR-T cells when encountering tumor cells expressing two target-antigens. Further, low doses of TanCAR-T cells could also effectively control the lung cancer and melanoma xenografts and improved overall survival of the treated animals. TanCAR-T cells targeting CD70 and B7-H3 exhibit enhanced antitumor functionality and improve the problem of antigenic heterogeneity and variant in the treatment against solid tumor and melanoma.
Topics: Animals; Antigens, Neoplasm; B7 Antigens; CD27 Ligand; Cell Line, Tumor; Female; Humans; Immunotherapy, Adoptive; Mice; Neoplasms; Receptors, Chimeric Antigen; Single-Chain Antibodies; T-Lymphocytes; Xenograft Model Antitumor Assays
PubMed: 32685008
DOI: 10.7150/thno.43991 -
Cell Jun 2022The isolation of CCoV-HuPn-2018 from a child respiratory swab indicates that more coronaviruses are spilling over to humans than previously appreciated. We determined...
The isolation of CCoV-HuPn-2018 from a child respiratory swab indicates that more coronaviruses are spilling over to humans than previously appreciated. We determined the structures of the CCoV-HuPn-2018 spike glycoprotein trimer in two distinct conformational states and showed that its domain 0 recognizes sialosides. We identified that the CCoV-HuPn-2018 spike binds canine, feline, and porcine aminopeptidase N (APN) orthologs, which serve as entry receptors, and determined the structure of the receptor-binding B domain in complex with canine APN. The introduction of an oligosaccharide at position N739 of human APN renders cells susceptible to CCoV-HuPn-2018 spike-mediated entry, suggesting that single-nucleotide polymorphisms might account for viral detection in some individuals. Human polyclonal plasma antibodies elicited by HCoV-229E infection and a porcine coronavirus monoclonal antibody inhibit CCoV-HuPn-2018 spike-mediated entry, underscoring the cross-neutralizing activity among ɑ-coronaviruses. These data pave the way for vaccine and therapeutic development targeting this zoonotic pathogen representing the eighth human-infecting coronavirus.
Topics: Animals; CD13 Antigens; Cats; Cell Line; Coronavirus; Coronavirus 229E, Human; Coronavirus Infections; Dogs; Humans; Receptors, Virus; Spike Glycoprotein, Coronavirus; Swine
PubMed: 35700730
DOI: 10.1016/j.cell.2022.05.019 -
Nature Immunology Sep 2022CD28 and CTLA-4 (CD152) play essential roles in regulating T cell immunity, balancing the activation and inhibition of T cell responses, respectively. Although both...
CD28 and CTLA-4 (CD152) play essential roles in regulating T cell immunity, balancing the activation and inhibition of T cell responses, respectively. Although both receptors share the same ligands, CD80 and CD86, the specific requirement for two distinct ligands remains obscure. In the present study, we demonstrate that, although CTLA-4 targets both CD80 and CD86 for destruction via transendocytosis, this process results in separate fates for CTLA-4 itself. In the presence of CD80, CTLA-4 remained ligand bound, and was ubiquitylated and trafficked via late endosomes and lysosomes. In contrast, in the presence of CD86, CTLA-4 detached in a pH-dependent manner and recycled back to the cell surface to permit further transendocytosis. Furthermore, we identified clinically relevant mutations that cause autoimmune disease, which selectively disrupted CD86 transendocytosis, by affecting either CTLA-4 recycling or CD86 binding. These observations provide a rationale for two distinct ligands and show that defects in CTLA-4-mediated transendocytosis of CD86 are associated with autoimmunity.
Topics: Antigens, CD; Antigens, Differentiation; B7-1 Antigen; B7-2 Antigen; CD28 Antigens; CTLA-4 Antigen; Cell Adhesion Molecules; Ligands; Lymphocyte Activation
PubMed: 35999394
DOI: 10.1038/s41590-022-01289-w -
Frontiers in Immunology 2022Efficient scanning of tissue that T cells encounter during their migratory life is pivotal to protective adaptive immunity. In fact, T cells can detect even a single... (Review)
Review
Efficient scanning of tissue that T cells encounter during their migratory life is pivotal to protective adaptive immunity. In fact, T cells can detect even a single antigenic peptide/MHC complex (pMHC) among thousands of structurally similar yet non-stimulatory endogenous pMHCs on the surface of antigen-presenting cells (APCs) or target cells. Of note, the glycocalyx of target cells, being composed of proteoglycans and bulky proteins, is bound to affect and even modulate antigen recognition by posing as a physical barrier. T cell-resident microvilli are actin-rich membrane protrusions that puncture through such barriers and thereby actively place the considerably smaller T-cell antigen receptors (TCRs) in close enough proximity to APC-presented pMHCs so that productive interactions may occur efficiently yet under force. We here review our current understanding of how the plasticity of T-cell microvilli and physicochemical properties of the glycocalyx may affect early events in T-cell activation. We assess insights gained from studies on T-cell plasma membrane ultrastructure and provide an update on current efforts to integrate biophysical aspects such as the amplitude and directionality of TCR-imposed mechanical forces and the distribution and lateral mobility of plasma membrane-resident signaling molecules into a more comprehensive view on sensitized T-cell antigen recognition.
Topics: Antigen-Presenting Cells; Antigens; Lymphocyte Activation; Protein Binding; Receptors, Antigen, T-Cell; T-Lymphocytes
PubMed: 35693808
DOI: 10.3389/fimmu.2022.886328 -
Immunity Mar 2021To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRβ chain sequences from 178 non-small cell lung cancer...
To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRβ chain sequences from 178 non-small cell lung cancer patients using the GLIPH2 (grouping of lymphocyte interactions with paratope hotspots 2) algorithm. We identified over 66,000 shared specificity groups, of which 435 were clonally expanded and enriched in tumors compared to adjacent lung. The antigenic epitopes of one such tumor-enriched specificity group were identified using a yeast peptide-HLA A02:01 display library. These included a peptide from the epithelial protein TMEM161A, which is overexpressed in tumors and cross-reactive epitopes from Epstein-Barr virus and E. coli. Our findings suggest that this cross-reactivity may underlie the presence of virus-specific T cells in tumor infiltrates and that pathogen cross-reactivity may be a feature of multiple cancers. The approach and analytical pipelines generated in this work, as well as the specificity groups defined here, present a resource for understanding the T cell response in cancer.
Topics: Algorithms; Antigen Presentation; Antigens, Neoplasm; Carcinoma, Non-Small-Cell Lung; Cells, Cultured; Cross Reactions; Epitope Mapping; Epitopes, T-Lymphocyte; HLA-A2 Antigen; Humans; Lung Neoplasms; Protein Binding; Receptors, Antigen, T-Cell, alpha-beta; T-Cell Antigen Receptor Specificity; T-Lymphocytes
PubMed: 33691136
DOI: 10.1016/j.immuni.2021.02.014