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| Open AccessEvidence for immune activation in pathogenesis of the HLA class II associated disease, podoconiosis
Podoconiosis is triggered by long term barefoot exposure to volcanic red clay soil. Here, Negash et al characterise the immune profile of podoconiosis patients to show this disease is associated with high levels of immune activation and inflammation.
- Mikias Negash
- , Menberework Chanyalew
- & Melanie J. Newport
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Article
| Open AccessAssessment of human leukocyte antigen-based neoantigen presentation to determine pan-cancer response to immunotherapy
HLA-I plays a key role in triggering an immune response and predicting immune checkpoint efficacy. Here the authors develop a method for quantifying HLA-I neoantigen presentation capacity by integrating HLA-I allele divergence and neoantigens numbers, termed HAPS, to describe how immune checkpoint response may be mediated by HLA.
- Jiefei Han
- , Yiting Dong
- & Zhijie Wang
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Article
| Open AccessHLA class I peptide polymorphisms contribute to class II DQβ0603:DQα0103 antibody specificity
Bead-based assays to assess the donor-specific antibody profile of solid organ transplant patients often produce discordant results relative to cell-based alternatives. In this study, the authors demonstrate that, for some MHC class-II-specific antibodies, discordance can be attributed to recognition of the MHC class-I-derived peptides bound to MHC class-II molecules.
- N. Remi Shih
- , Thoa Nong
- & Jar-How Lee
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Article
| Open Accessp53 suppresses MHC class II presentation by intestinal epithelium to protect against radiation-induced gastrointestinal syndrome
Radiation induced gastrointestinal syndrome is a complication of radiotherapy and the tumor suppressor p53 is implicated in protection from gastrointestinal toxicity. Here Wang and colleagues show that p53 protection against radiation-induced gastrointestinal syndrome involves intestinal stem cell function and inhibition of inflammation triggered by radiation via the IL12- p40/MHC-II axis.
- Jianming Wang
- , Chun-Yuan Chang
- & Wenwei Hu
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Article
| Open AccessTOFIMS mass spectrometry-based immunopeptidomics refines tumor antigen identification
MS-based immunopeptidomics provides direct evidence for HLA peptide-antigen presentation, which is indispensable for therapeutic use. Here the authors present an ion mobility MS-based immunopeptidome workflow, largely expand benign reference databases and enables next generation tumor antigen discovery.
- Naomi Hoenisch Gravel
- , Annika Nelde
- & Juliane S. Walz
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Article
| Open AccessCrystal structures of MHC class I complexes reveal the elusive intermediate conformations explored during peptide editing
The unusual crystal structures of MHC I-peptide complexes provide a visualization of the remarkable ability of the groove to adapt conformationally to bound peptides, explaining how MHC I molecules edit peptides in antigen presentation.
- Lenong Li
- , Xubiao Peng
- & Marlene Bouvier
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Article
| Open AccessHigh-throughput characterization of HLA-E-presented CD94/NKG2x ligands reveals peptides which modulate NK cell activation
HLA-E is a highly conserved MHC-l recognized by NK and T cells. The authors characterize HLA-E-presented peptides recognized by CD94/NKG2x, identifying human and CMV-derived peptide ligands which can modulate NK cell activity when presented by HLA-E, including for selective NK cell activation.
- Brooke D. Huisman
- , Ning Guan
- & Michael E. Birnbaum
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Article
| Open AccessMolecular mechanism of phosphopeptide neoantigen immunogenicity
Phosphorylated peptide antigens are present on cancer cells, but their role in cancer immunity is unknown. Here, the authors describe a molecular mechanism, by which a tumor-specific phosphopeptide found in acute myeloid leukemia is recognized by the human immune T cells.
- Yury Patskovsky
- , Aswin Natarajan
- & Michelle Krogsgaard
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Article
| Open AccessUnraveling the glycosylated immunopeptidome with HLA-Glyco
Protein glycosylation plays a vital role in antigen recognition and immune modulation. Here, the authors present a computational workflow for identifying glycosylated peptides from mass spectrometry-based immunopeptidome data and investigate the properties of glycosylated MHC associated peptides.
- Georges Bedran
- , Daniel A. Polasky
- & Alexey I. Nesvizhskii
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Article
| Open AccessSARS-CoV-2 escape from cytotoxic T cells during long-term COVID-19
Here, the authors report accelerated intrahost evolution of SARS-CoV-2 in an immunocompromised patient with non-Hodgkin’s lymphoma with 318 days long COVID-19, and show that changes in the viral genome resulted in escape from T cellular immune response.
- Oksana V. Stanevich
- , Evgeniia I. Alekseeva
- & Georgii A. Bazykin
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Article
| Open AccessCD1a promotes systemic manifestations of skin inflammation
Skin inflammation is often accompanied by systemic disease, yet the pathways that regulate this escalation are little known. Here authors show that transgenic expression of human CD1a in mice leads to the escalation of experimental skin inflammation and systemic inflammatory disease, and the generalized symptoms could be alleviated by blocking antibodies developed against CD1a.
- Clare S. Hardman
- , Yi-Ling Chen
- & Graham S. Ogg
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Article
| Open AccessA conserved population of MHC II-restricted, innate-like, commensal-reactive T cells in the gut of humans and mice
Interactions between the host immune response and the commensal microbiota play essential roles in health and disease. Here the authors identify a population of MHC class II, innate like, commensal reactive cells in the gut of mice and humans.
- Carl-Philipp Hackstein
- , Dana Costigan
- & Emily E. Thornton
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Article
| Open AccessA class-mismatched TCR bypasses MHC restriction via an unorthodox but fully functional binding geometry
MHC restriction depicts CD4+ T cell activation by MHC-II and CD8A+ by MHC-I, but rare T cells with mismatched MHC restriction have been reported. Here the authors use crystallography to describe features of such a mismatched TCR-MHC interaction and implicate an atypical TCR structure and TCR-MHC interface as contributing factors.
- Nishant K. Singh
- , Jesus A. Alonso
- & Brian M. Baker
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| Open AccessAblation of CD8+ T cell recognition of an immunodominant epitope in SARS-CoV-2 Omicron variants BA.1, BA.2 and BA.3
The T cell response to SARS-CoV-2 is important in protection from infection. Here the authors show by concentrating on a specific HLA haplotype that mutations in SARS-CoV-2 as new variants emerge can affect T cell recognition and reduce T cell responses to the virus.
- Srividhya Swaminathan
- , Katie E. Lineburg
- & Corey Smith
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Article
| Open AccessStructure of an MHC I–tapasin–ERp57 editing complex defines chaperone promiscuity
Adaptive immunity depends on cellular chaperone and quality control systems that are decisive for an effective presentation of foreign antigens via MHC I molecules. Here, the authors present the structure of a key chaperone-MHC I complex.
- Ines Katharina Müller
- , Christian Winter
- & Robert Tampé
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Article
| Open AccessMolecular basis of MHC I quality control in the peptide loading complex
The immune system monitors the health status of cells by surveilling fragments of foreign molecules from invaders presented on MHC I complexes at the cell surface. Here, the authors investigate the sequence of events of MHC I assembly and quality control cycle.
- Alexander Domnick
- , Christian Winter
- & Robert Tampé
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Article
| Open AccessUbiquitin-like protein 3 (UBL3) is required for MARCH ubiquitination of major histocompatibility complex class II and CD86
Regulated trafficking of major histocompatibility complex class II and CD86 is a prerequisite of antigen presenting cell functionality. Authors show here that ubiquitin-like protein 3 is critically involved in the ubiquitination process that controls trafficking, with wide-ranging immunological consequences.
- Haiyin Liu
- , Kayla R. Wilson
- & Justine D. Mintern
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Article
| Open AccessMesenchymal stem cells transfer mitochondria to allogeneic Tregs in an HLA-dependent manner improving their immunosuppressive activity
Regulatory T (Treg) cells and mesenchymal stem cells (MSCs) are both cell populations capable of immune tolerance induction. Here the authors show that the transfer of mitochondria from mesenchymal stem cells to allogeneic Treg cells in an HLA-dependent manner results in enhanced immunosuppressive functions of Treg cells.
- Karolina Piekarska
- , Zuzanna Urban-Wójciuk
- & Natalia Maria Marek-Trzonkowska
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Article
| Open AccessCD4 and CD8 co-receptors modulate functional avidity of CD1b-restricted T cells
CD4 and CD8 co-receptors are routinely used to define distinct functional and phenotypic lineages of T cells. Here the authors show CD4 and CD8 also modulate the functional avidity of the CD1b-restricted response to mycobacterial lipid antigens
- Charlotte A. James
- , Yuexin Xu
- & Chetan Seshadri
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Article
| Open AccessSARS-CoV-2 inhibits induction of the MHC class I pathway by targeting the STAT1-IRF1-NLRC5 axis
The presentation of viral antigens to T cells via the MHC molecules is a critical component of the host response to viral infection. Here the authors suggest SARS-CoV-2 possesses the immune evasion strategy against the MHC class I pathway by targeting key transcriptional regulators.
- Ji-Seung Yoo
- , Michihito Sasaki
- & Koichi S. Kobayashi
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Article
| Open AccessExchange catalysis by tapasin exploits conserved and allele-specific features of MHC-I molecules
Tapasin is part of the peptide loading complex necessary for presenting antigenic peptides on MHC-I for the induction of adaptive immunity. Here the authors show that tapasin interacts with MHC-I in both conserved and allele-specific regions to promote antigen presentation, with tapasin L18 and K16 residues both implicated in this molecular interaction.
- Huan Lan
- , Esam T. Abualrous
- & Christian Freund
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Article
| Open AccessDeep learning boosts sensitivity of mass spectrometry-based immunopeptidomics
The identification of HLA peptides by mass spectrometry is non-trivial. Here, the authors extended and used the wealth of data from the ProteomeTools project to improve the prediction of non-tryptic peptides using deep learning, and show their approach enables a variety of immunological discoveries.
- Mathias Wilhelm
- , Daniel P. Zolg
- & Bernhard Kuster
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Article
| Open AccessTAPBPR promotes antigen loading on MHC-I molecules using a peptide trap
The molecular chaperones tapasin and TAPBPR play important roles in defining the repertoire of peptides displayed by MHC class I. Here, the authors combine NMR, ITC, fluorescence polarization measurements and deep mutational scanning analyses to reveal a peptide editing mechanism, where the G24-R36 loop in TAPBPR acts as a molecular trap to promote the selection of high-affinity peptide cargo.
- Andrew C. McShan
- , Christine A. Devlin
- & Nikolaos G. Sgourakis
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Article
| Open AccessCD8+ T cell landscape in Indigenous and non-Indigenous people restricted by influenza mortality-associated HLA-A*24:02 allomorph
The immunology of Indigenous populations is generally understudied outside the context of diseases that are prevalent in these communities. Here the authors identify prevalence of influenza CD8+ T cell epitopes in an Indigenous Australian population expressing the susceptibility allomorph HLA A*24:02 and validate immunodominance of some of these epitopes in mice.
- Luca Hensen
- , Patricia T. Illing
- & Katherine Kedzierska
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Article
| Open AccessClassical MHC expression by DP thymocytes impairs the selection of non-classical MHC restricted innate-like T cells
Conventional T cell subsets are selected in the thymus by peptide bearing MHC expressed by cortical epithelial cells, in contrast cortical thymocytes express non-peptide bearing MHC molecules including CD1d and MR1 and select iNKT and MAIT cell populations respectively. Here, the authors generate a novel inducible MHC class-I trasnactivator murine system and suggest the absence of peptide-MHC on thymocytes is involved in the selection of non-peptide specific lymphocytes.
- Hristo Georgiev
- , Changwei Peng
- & Kristin A. Hogquist
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Article
| Open AccessOxidation inhibits autophagy protein deconjugation from phagosomes to sustain MHC class II restricted antigen presentation
LC3-associated phagocytosis (LAP) is a non-canonical use of the autophagy machinery that can contribute to immune responses. Here, the authors describe the mechanism by which ROS production regulates LAPosome stabilization sustaining MHC II dependent antigen presentation.
- Laure-Anne Ligeon
- , Maria Pena-Francesch
- & Christian Münz
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Article
| Open AccessThermostability profiling of MHC-bound peptides: a new dimension in immunopeptidomics and aid for immunotherapy design
Thermostability of the peptide-MHC interaction is important for immunogenicity. Here the authors present a mass spectrometry method to measure thermostability among thousands of peptide-MHC complexes in parallel and a trained artificial neural network to predict immunogenenicity of cancer antigens.
- Emma C. Jappe
- , Christian Garde
- & Anthony W. Purcell
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Article
| Open AccessHuman endogenous retroviruses form a reservoir of T cell targets in hematological cancers
Human endogenous retroviruses (HERV) normally remain quiescent, but can be reactivated by malignant transformation. Here the authors find, via HERV peptide library testing and tetramer validation, more profound HERV transcription and associated T cell recognition in myeloid cancer patients to implicate HERVs as potential therapeutic targets.
- Sunil Kumar Saini
- , Andreas Due Ørskov
- & Sine Reker Hadrup
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Article
| Open AccessRepertoire-scale determination of class II MHC peptide binding via yeast display improves antigen prediction
Identifying peptides that can bind major histocompatibility complex II (MHC-II) is important for our understanding of T cell immunity and specificity. Here the authors present a yeast-display library screening approach that identifies more potential binders than various reported algorithms to help expand our understanding for antigen presentation.
- C. Garrett Rappazzo
- , Brooke D. Huisman
- & Michael E. Birnbaum
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Article
| Open AccessMultiplexed relative and absolute quantitative immunopeptidomics reveals MHC I repertoire alterations induced by CDK4/6 inhibition
Immunopeptidomics allows identifying the cellular repertoire of MHC-bound peptides, but quantifying them remains challenging. Here, the authors present a method to efficiently generate internal peptide MHC standards and calibration curves, facilitating relative and absolute quantitative immunopeptidomics.
- Lauren E. Stopfer
- , Joshua M. Mesfin
- & Forest M. White
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Article
| Open AccessHigh throughput pMHC-I tetramer library production using chaperone-mediated peptide exchange
Peptide-MHC (pMHC) tetramers are important tools for probing T cell repertoire and adaptive immune responses. Here the authors use a molecular chaperone, TAPBPR, to develop a high-throughput, multiplexible platform for pMHC tetramer generation to facilitate simultaneous assessments of T cell repertoire/antigen specificity and transcriptome.
- Sarah A. Overall
- , Jugmohit S. Toor
- & Nikolaos G. Sgourakis
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Article
| Open AccessStructures of peptide-free and partially loaded MHC class I molecules reveal mechanisms of peptide selection
Major Histocompatibility Complex (MHC) class I molecules present tightly binding peptides on the cell surface for recognition by cytotoxic T cells. Here, the authors present the crystal structures of a disulfide-stabilized human MHC class I molecule in the peptide-free state and bound with dipeptides, and find that peptide binding is accompanied by concerted conformational switches of the amino acid side chains in the binding pockets.
- Raghavendra Anjanappa
- , Maria Garcia-Alai
- & Rob Meijers
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Article
| Open AccessImmunoproteasome expression is associated with better prognosis and response to checkpoint therapies in melanoma
The response to immunotherapy of melanoma patients is heterogeneous. Here, the authors demonstrate that a high expression of the two major components of the immunoproteasome, PSMB8 and PSMB9, modulates the production of HLA peptides and it is predictive of better survival and improved response to immune-checkpoint inhibitors of melanoma patients.
- Shelly Kalaora
- , Joo Sang Lee
- & Yardena Samuels
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Article
| Open AccessDistinct CD1d docking strategies exhibited by diverse Type II NKT cell receptors
Natural killer T (NKT) cells include type I that express semi-invariant T cell receptor (TCR), and type II that cover a broader repertoire. Here the authors describe the crystal structure of a type II NKT TCR complexed with CD1d/antigen to propose that type II NKT TCRs may adapt multiple CD1d docking modes to maximise antigen recognition efficacy.
- Catarina F. Almeida
- , Srinivasan Sundararaj
- & Jamie Rossjohn
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Article
| Open AccessRapid selection and identification of functional CD8+ T cell epitopes from large peptide-coding libraries
High-throughput assays for TCR specificity are a bottleneck in understanding T cell immunity and harnessing it for medicine. Here the authors develop a functional screening method to identify T cell specificity in the natural context of peptide-MHC presentation, enabling detection of physiologically relevant T cell antigens from large libraries of peptide-coding sequences.
- Govinda Sharma
- , Craig M. Rive
- & Robert A. Holt
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Article
| Open AccessMolecular constraints on CDR3 for thymic selection of MHC-restricted TCRs from a random pre-selection repertoire
For T cells, functional antigen receptors are selected in the thymus from a pre-selection repertoire by interaction with self MHCs. Here the authors show that specific, non-germline coded features located in the complementarity determining region 3 of the pre-selection antigen receptors are essential for the selection of MHC-restricted repertoire.
- Jinghua Lu
- , François Van Laethem
- & Peter D. Sun
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Article
| Open AccessDefining the structural basis for human alloantibody binding to human leukocyte antigen allele HLA-A*11:01
Anti-human leukocyte antigen (HLA) antibodies are important mediators of alloresponses, but structural insights on antibody:HLA interaction are still lacking. Here the authors provide a 2.4 Å structure of antibody:HLA complex, and also analyse HLA features important for other HLA-interacting molecules, to enhance our understanding of alloimmunity.
- Yue Gu
- , Yee Hwa Wong
- & Paul A. MacAry
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Article
| Open AccessHLA-B57 micropolymorphism defines the sequence and conformational breadth of the immunopeptidome
Human leukocyte antigens (HLA) are multi-allelic and polymorphic genes that present antigens to immune cells for inducing protective immunity. Here, using systems biology and structural approaches, the authors show that micropolymorphism of three HLA has effects beyond the modulation of antigen diversity.
- Patricia T. Illing
- , Phillip Pymm
- & Anthony W. Purcell
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Article
| Open AccessAcquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA
Acquired resistance is a major problem in cancer immunotherapy. Here the authors report a study of two patients with Merkel cell carcinoma under immunotherapy treatment who develop resistance after deep responses for >1 year and identified a novel mechanism of acquired, gene-specific transcriptional suppression of HLAs.
- K. G. Paulson
- , V. Voillet
- & A. G. Chapuis
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Article
| Open AccessPathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding
Human leucocyte antigen E (HLA-E) directly engages NK cells but also presents antigen to CD8+ T cells. Here the authors show crystal structures of HLA-E in complex with peptides derived from HIV and Mycobacterium tuberculosis, and describe binding conformations, the positional impact of residues involved and discuss implications for functional presentation to CD8+ T cells.
- Lucy C. Walters
- , Karl Harlos
- & Geraldine M. Gillespie
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Article
| Open AccessNonstimulatory peptide–MHC enhances human T-cell antigen-specific responses by amplifying proximal TCR signaling
Coagonism, the ability of nonstimulatory antigens to promote T-cell activation, has been reported in mice. Here the authors show that coagonism also occurs in human CD8 T cells, in which a nonstimulatory HIV GAG peptide enhances a specific T-cell response to a hepatitis B virus epitope by amplifying T-cell receptor signals.
- Xiang Zhao
- , Shvetha Sankaran
- & Nicholas R. J. Gascoigne
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Article
| Open AccessNon-equivalent antigen presenting capabilities of dendritic cells and macrophages in generating brain-infiltrating CD8 + T cell responses
Dendritic cell antigen presentation is central to CD8+ T cell responses, but surprisingly little is known about the requirement for this functionality in the central nervous system. Here, the authors use three different models of neuroinflammation to show the importance of these cells in the CNS and in response to cerebral malaria, picornavirus infection and experimental glioma.
- Courtney S. Malo
- , Matthew A. Huggins
- & Aaron J. Johnson
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Article
| Open AccessAdipocyte adaptive immunity mediates diet-induced adipose inflammation and insulin resistance by decreasing adipose Treg cells
Obesity is associated with inflammation in adipose tissue, characterized by a shift in local T cell subsets. Here the authors show that loss of MHCII expression on adipocytes increases levels of immunosuppressive regulatory T cells in adipose tissue, which enhances insulin sensitivity.
- Tuo Deng
- , Joey Liu
- & Willa A. Hsueh
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Article
| Open AccessHLA-DP84Gly constitutively presents endogenous peptides generated by the class I antigen processing pathway
MHC class I and II molecules generally present endogenous and exogenous peptides, respectively, through distinct mechanisms. Here, the authors show that the class II molecule HLA-DP84Glyuses both class I and II mechanisms to constitutively present peptides.
- Yuki Yamashita
- , Mark Anczurowski
- & Naoto Hirano
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Article
| Open AccessCD45-mediated control of TCR tuning in naïve and memory CD8+ T cells
Naïve T cells establish self-tolerance via negative selection of cells with strong reactivity for self-peptide/MHC complexes, but undergo T-cell receptor (TCR) desensitisation when leaving the thymus. Here, Choet al.show that TCR desensitisation correlates with cell-surface density of the phosphatase CD45.
- Jae-Ho Cho
- , Hee-Ok Kim
- & Jonathan Sprent
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Article
| Open AccessMHC class II complexes sample intermediate states along the peptide exchange pathway
MHCII proteins bind and present both foreign and self-antigens to potentially activate CD4+ T cells via cognate T cell receptors (TCRs) during the adaptive immune response. Here, the authors combine NMR-detected H/D exchange with Markov modelling analysis to shed light on the dynamics of MHCII peptide exchange.
- Marek Wieczorek
- , Jana Sticht
- & Christian Freund
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Article
| Open AccessEfficient generation of monoclonal antibodies against peptide in the context of MHCII using magnetic enrichment
Generating antibodies specific for the peptide–MHCII complexes has been challenging, with only a handful made to date. Here, the authors develop a more efficient approach to generate these antibodies, and demonstrate their potential in research and therapeutic applications.
- Justin A. Spanier
- , Daniel R. Frederick
- & Brian T. Fife
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Article
| Open AccessMelanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy
Immunotherapy is used to treat melanoma, however patient responses vary widely highlighting the need for factors that can predict therapeutic success. Here, the authors show that MHC-II molecules expressed by tumour cells are positively correlated with a good response to therapy and overall patient survival.
- Douglas B. Johnson
- , Monica V. Estrada
- & Justin M. Balko
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Article
| Open AccessCrystal structure of the N-myristoylated lipopeptide-bound MHC class I complex
Lipid antigens have been added to the antigenic repertoire in recent years. Here, the authors have identified Mamu-B*098 as a lipopeptide antigen presenting molecule and using structural and biochemical analysis have shown that it has a different antigen binding pocket to previously analysed proteins.
- Daisuke Morita
- , Yukie Yamamoto
- & Masahiko Sugita