Diversification of CD1 molecules shapes lipid antigen selectivity

Abstract Molecular studies of host-pathogen evolution have largely focused on the consequences of variation at protein-protein interaction surfaces. The potential for other microbe-associated macromolecules to promote arms race dynamics with host factors remains unclear. The cluster of differentiation 1 (CD1) family of vertebrate cell surface receptors plays a crucial role in adaptive immunity through binding and presentation of lipid antigens to T-cells. Although CD1 proteins present a variety of endogenous and microbial lipids to various T-cell types, they are less diverse within vertebrate populations than the related major histocompatibility complex (MHC) molecules. We discovered that CD1 genes exhibit a high level of divergence between simian primate species, altering predicted lipid binding properties and T-cell receptor (TCR) interactions. These findings suggest that lipid-protein conflicts have shaped CD1 genetic variation during primate evolution. Consistent with this hypothesis, multiple primate CD1 family proteins exhibit signatures of repeated positive selection at surfaces impacting antigen presentation, binding pocket morphology, and TCR accessibility. Using a molecular modeling approach, we observe that inter-species variation as well as single mutations at rapidly-evolving sites in CD1a drastically alter predicted lipid binding and structural features of the T-cell recognition surface. We further show that alterations in both endogenous and microbial lipid binding affinities influence the ability of CD1a to undergo antigen swapping required for T-cell activation. Together these findings establish lipid-protein interactions as a critical force of host-pathogen conflict and inform potential strategies for lipid-based vaccine development.

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Diversification of CD1 molecules shapes lipid antigen selectivity

10.1101/2020.11.10.377556 ◽

2020 ◽

Author(s):

Nicole M. Paterson ◽

Hussein Al-Zubieri ◽

Matthew F. Barber

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Vaccine Development ◽

Structural Features ◽

Lipid Binding ◽

Primate Species ◽

Species Variation ◽

Mhc Molecules ◽

Host Pathogen

AbstractMolecular studies of host-pathogen evolution have largely focused on the consequences of variation at protein-protein interaction surfaces. The potential for other microbe-associated macromolecules to promote arms race dynamics with host factors remains unclear. The cluster of differentiation 1 (CD1) family of vertebrate cell surface receptors plays a crucial role in adaptive immunity through binding and presentation of lipid antigens to T-cells. Although CD1 proteins present a variety of endogenous and microbial lipids to various T-cell types, they are less diverse within vertebrate populations than the related major histocompatibility complex (MHC) molecules. We discovered that CD1 genes exhibit a high level of divergence between simian primate species, altering predicted lipid binding properties and T-cell receptor (TCR) interactions. These findings suggest that lipid-protein conflicts have shaped CD1 genetic variation during primate evolution. Consistent with this hypothesis, multiple primate CD1 family proteins exhibit signatures of repeated positive selection at surfaces impacting antigen presentation, binding pocket morphology, and TCR accessibility. Using a molecular modeling approach, we observe that inter-species variation as well as single mutations at rapidly-evolving sites in CD1a drastically alter predicted lipid binding and structural features of the T-cell recognition surface. We further show that alterations in both endogenous and microbial lipid binding affinities influence the ability of CD1a to undergo antigen swapping required for T-cell activation. Together these findings establish lipid-protein interactions as a critical force of host-pathogen conflict and inform potential strategies for lipid-based vaccine development.

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HLA-Arena: A Customizable Environment for the Structural Modeling and Analysis of Peptide-HLA Complexes for Cancer Immunotherapy

JCO Clinical Cancer Informatics ◽

10.1200/cci.19.00123 ◽

2020 ◽

pp. 623-636 ◽

Cited By ~ 3

Author(s):

Dinler A. Antunes ◽

Jayvee R. Abella ◽

Sarah Hall-Swan ◽

Didier Devaurs ◽

Anja Conev ◽

...

Keyword(s):

T Cell ◽

Cancer Immunotherapy ◽

T Cell Activation ◽

Large Scale ◽

Cell Activation ◽

Vaccine Development ◽

Structural Modeling ◽

Structural Features ◽

Binding Prediction ◽

Modeling And Analysis

PURPOSE HLA protein receptors play a key role in cellular immunity. They bind intracellular peptides and display them for recognition by T-cell lymphocytes. Because T-cell activation is partially driven by structural features of these peptide-HLA complexes, their structural modeling and analysis are becoming central components of cancer immunotherapy projects. Unfortunately, this kind of analysis is limited by the small number of experimentally determined structures of peptide-HLA complexes. Overcoming this limitation requires developing novel computational methods to model and analyze peptide-HLA structures. METHODS Here we describe a new platform for the structural modeling and analysis of peptide-HLA complexes, called HLA-Arena, which we have implemented using Jupyter Notebook and Docker. It is a customizable environment that facilitates the use of computational tools, such as APE-Gen and DINC, which we have previously applied to peptide-HLA complexes. By integrating other commonly used tools, such as MODELLER and MHCflurry, this environment includes support for diverse tasks in structural modeling, analysis, and visualization. RESULTS To illustrate the capabilities of HLA-Arena, we describe 3 example workflows applied to peptide-HLA complexes. Leveraging the strengths of our tools, DINC and APE-Gen, the first 2 workflows show how to perform geometry prediction for peptide-HLA complexes and structure-based binding prediction, respectively. The third workflow presents an example of large-scale virtual screening of peptides for multiple HLA alleles. CONCLUSION These workflows illustrate the potential benefits of HLA-Arena for the structural modeling and analysis of peptide-HLA complexes. Because HLA-Arena can easily be integrated within larger computational pipelines, we expect its potential impact to vastly increase. For instance, it could be used to conduct structural analyses for personalized cancer immunotherapy, neoantigen discovery, or vaccine development.

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MHCII glycosylation modulates Bacteroides fragilis carbohydrate antigen presentation

Journal of Experimental Medicine ◽

10.1084/jem.20100508 ◽

2011 ◽

Vol 208 (5) ◽

pp. 1041-1053 ◽

Cited By ~ 28

Author(s):

Sean O. Ryan ◽

Jason A. Bonomo ◽

Fan Zhao ◽

Brian A. Cobb

Keyword(s):

T Cells ◽

T Cell ◽

Antigen Presentation ◽

T Cell Activation ◽

Cell Activation ◽

Bacteroides Fragilis ◽

Carbohydrate Antigen ◽

Activated T Cells ◽

Mhc Molecules

N-linked glycans are thought to protect class II major histocompatibility complex (MHC) molecules (MHCII) from proteolytic cleavage and assist in arranging proteins within the immune synapse, but were not thought to directly participate in antigen presentation. Here, we report that antigen-presenting cells (APCs) lacking native complex N-glycans showed reduced MHCII binding and presentation of the T cell activating glycoantigen (GlyAg) polysaccharide A from Bacteroides fragilis but not conventional peptides. APCs lacking native N-glycans also failed to mediate GlyAg-driven T cell activation but activated T cells normally with protein antigen. Mice treated with the mannosidase inhibitor kifunensine to prevent the formation of complex N-glycans were unable to expand GlyAg-specific T cells in vivo upon immunization, yet adoptive transfer of normally glycosylated APCs into these animals overcame this defect. Our findings reveal that MHCII N-glycosylation directly impacts binding and presentation of at least one class of T cell–dependent antigen.

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Structure-based Methods for Binding Mode and Binding Affinity Prediction for Peptide-MHC Complexes

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666181224101744 ◽

2019 ◽

Vol 18 (26) ◽

pp. 2239-2255 ◽

Cited By ~ 13

Author(s):

Dinler A. Antunes ◽

Jayvee R. Abella ◽

Didier Devaurs ◽

Maurício M. Rigo ◽

Lydia E. Kavraki

Keyword(s):

Immune Response ◽

T Cell ◽

Binding Affinity ◽

T Cell Activation ◽

Cell Activation ◽

Vaccine Development ◽

Structural Modeling ◽

Binding Mode ◽

Binding Affinity Prediction ◽

Affinity Prediction

Understanding the mechanisms involved in the activation of an immune response is essential to many fields in human health, including vaccine development and personalized cancer immunotherapy. A central step in the activation of the adaptive immune response is the recognition, by T-cell lymphocytes, of peptides displayed by a special type of receptor known as Major Histocompatibility Complex (MHC). Considering the key role of MHC receptors in T-cell activation, the computational prediction of peptide binding to MHC has been an important goal for many immunological applications. Sequence- based methods have become the gold standard for peptide-MHC binding affinity prediction, but structure-based methods are expected to provide more general predictions (i.e., predictions applicable to all types of MHC receptors). In addition, structural modeling of peptide-MHC complexes has the potential to uncover yet unknown drivers of T-cell activation, thus allowing for the development of better and safer therapies. In this review, we discuss the use of computational methods for the structural modeling of peptide-MHC complexes (i.e., binding mode prediction) and for the structure-based prediction of binding affinity.

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Targeting of antigens to B cells augments antigen-specific T-cell responses and breaks immune tolerance to tumor-associated antigen MUC1

Blood ◽

10.1182/blood-2008-05-157396 ◽

2008 ◽

Vol 112 (7) ◽

pp. 2817-2825 ◽

Cited By ~ 25

Author(s):

Chuanlin Ding ◽

Li Wang ◽

Jose Marroquin ◽

Jun Yan

Keyword(s):

T Cell ◽

B Cells ◽

T Cell Activation ◽

Cell Activation ◽

Vaccine Development ◽

High Titer ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses

Abstract B cells are antibody (Ab)–secreting cells as well as potent antigen (Ag)–presenting cells that prime T-cell activation, which evokes great interest in their use for vaccine development. Here, we targeted ovalbumin (OVA) to B cells via CD19 and found that a single low dose of anti–CD19-OVA conjugates, but not isotype mAb-OVA, stimulated augmented CD4 and CD8 T-cell proliferation and expansion. Administration of TLR9 agonist CpG could significantly enhance long-term T-cell survival. Similar results were obtained when the tumor-associated Ag MUC1 was delivered to B cells. MUC1 transgenic (Tg) mice were previously found to lack effective T-cell help and produce low-titer of anti-MUC1 Abs after vaccination. Targeting MUC1 to B cells elicited high titer of anti-MUC1 Abs with different isotypes, predominantly IgG2a and IgG2b, in MUC1 Tg mice. The isotype switching of anti-MUC1 Ab was CD4 dependent. In addition, IFN-γ–producing CD8 T cells and in vivo cytolytic activity were significantly increased in these mice. The mice also showed significant resistance to MUC1+ lymphoma cell challenge both in the prophylactic and therapeutic settings. We conclude that Ags targeting to B cells stimulate CD4 and CD8 T-cell responses as well as Th-dependent humoral immune responses.

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The CD43 130-kD peripheral T-cell activation antigen is downregulated in thymic positive selection

Blood ◽

10.1182/blood.v88.5.1725.1725 ◽

1996 ◽

Vol 88 (5) ◽

pp. 1725-1732 ◽

Cited By ~ 30

Author(s):

LG Ellies ◽

W Tao ◽

W Fellinger ◽

HS Teh ◽

HJ Ziltener

Keyword(s):

T Cells ◽

T Cell ◽

Positive Selection ◽

T Cell Activation ◽

Cell Activation ◽

Class Ii ◽

Class I ◽

Double Positive ◽

Mhc Molecules ◽

Activation Antigen

Abstract Specific glycoforms of CD43, the major O-glycosylated cell-surface protein on T lymphocytes, can affect cell adhesion according to the types of carbohydrate side chains carried. In the peripheral immune system, CD43 130 kD, which carries core 2 O-glycan structures on its surface, is an activation antigen expressed on both CD4 and CD8 single- positive (SP) T cells. We have previously shown that the 115-kD resting and 130-kD activation glycoforms of murine CD43 are differentially regulated on peripheral SP T cells. In this study, we used transgenic mice expressing T-cell receptors (TCRs) specific for antigens presented by class I and class II major histocompatibility complex (MHC) molecules to determine whether CD43 glycoforms are involved in thymocyte differentiation. Positive selection in these mice results in an increase in the production of CD8 and CD4 SP T cells, respectively, which express the transgenic TCR. Positive selection is also accompanied by the upregulation of TCR, CD69, and CD5. Using these markers to define stages of thymocyte maturation, we found that CD43 130 kD was downregulated in the positive selection of CD4 CD8 double- positive thymocytes expressing a class I but not class II MHC- restricted TCR. These data suggest that core 2 glycosyltransferase (C2GnT) modulated expression of CD43 glycoforms may be involved in thymic selection events.

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The CD43 130-kD peripheral T-cell activation antigen is downregulated in thymic positive selection

Blood ◽

10.1182/blood.v88.5.1725.bloodjournal8851725 ◽

1996 ◽

Vol 88 (5) ◽

pp. 1725-1732 ◽

Cited By ~ 1

Author(s):

LG Ellies ◽

W Tao ◽

W Fellinger ◽

HS Teh ◽

HJ Ziltener

Keyword(s):

T Cells ◽

T Cell ◽

Positive Selection ◽

T Cell Activation ◽

Cell Activation ◽

Class Ii ◽

Class I ◽

Double Positive ◽

Mhc Molecules ◽

Activation Antigen

Specific glycoforms of CD43, the major O-glycosylated cell-surface protein on T lymphocytes, can affect cell adhesion according to the types of carbohydrate side chains carried. In the peripheral immune system, CD43 130 kD, which carries core 2 O-glycan structures on its surface, is an activation antigen expressed on both CD4 and CD8 single- positive (SP) T cells. We have previously shown that the 115-kD resting and 130-kD activation glycoforms of murine CD43 are differentially regulated on peripheral SP T cells. In this study, we used transgenic mice expressing T-cell receptors (TCRs) specific for antigens presented by class I and class II major histocompatibility complex (MHC) molecules to determine whether CD43 glycoforms are involved in thymocyte differentiation. Positive selection in these mice results in an increase in the production of CD8 and CD4 SP T cells, respectively, which express the transgenic TCR. Positive selection is also accompanied by the upregulation of TCR, CD69, and CD5. Using these markers to define stages of thymocyte maturation, we found that CD43 130 kD was downregulated in the positive selection of CD4 CD8 double- positive thymocytes expressing a class I but not class II MHC- restricted TCR. These data suggest that core 2 glycosyltransferase (C2GnT) modulated expression of CD43 glycoforms may be involved in thymic selection events.

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Structural insight into T cell coinhibition by PD-1H (VISTA)

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1908711117 ◽

2020 ◽

Vol 117 (3) ◽

pp. 1648-1657 ◽

Cited By ~ 3

Author(s):

Benjamin T. Slater ◽

Xue Han ◽

Lieping Chen ◽

Yong Xiong

Keyword(s):

T Cell ◽

T Cell Activation ◽

Molecular Basis ◽

Cell Activation ◽

Inflammatory Diseases ◽

Variable Region ◽

Structural Features ◽

Proximal Half ◽

Programmed Death 1 ◽

Insight Into

Programmed death-1 homolog (PD-1H), a CD28/B7 family molecule, coinhibits T cell activation and is an attractive immunotherapeutic target for cancer and inflammatory diseases. The molecular basis of its function, however, is unknown. Bioinformatic analyses indicated that PD-1H has a very long Ig variable region (IgV)-like domain and extraordinarily high histidine content, suggesting that unique structural features may contribute to coinhibitory mechanisms. Here we present the 1.9-Å crystal structure of the human PD-1H extracellular domain. It reveals an elongated CC′ loop and a striking concentration of histidine residues, located in the complementarity-determining region-like proximal half of the molecule. We show that surface-exposed histidine clusters are essential for robust inhibition of T cell activation. PD-1H exhibits a noncanonical IgV-like topology including an extra “H” β-strand and “clamping” disulfide, absent in known IgV-like structures, that likely restricts its orientation on the cell surface differently from other IgV-like domains. These results provide important insight into a molecular basis of T cell coinhibition by PD-1H.

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A phosphatidylinositol-linkage-deficient T-cell mutant contains insulin-sensitive glycosyl-phosphatidylinositol

Biochemical Journal ◽

10.1042/bj2820681 ◽

1992 ◽

Vol 282 (3) ◽

pp. 681-686 ◽

Cited By ~ 6

Author(s):

M A Avila ◽

R Clemente ◽

I Varela-Nieto

Keyword(s):

T Cell ◽

Cell Lines ◽

T Cell Activation ◽

Time Course ◽

Cell Activation ◽

Cell Receptor ◽

Structural Features ◽

Glycosyl Phosphatidylinositol ◽

Anchoring Proteins ◽

Insulin Responsiveness

Glycosyl-phosphatidylinositol molecules, acting as both signal transduction elements and membrane protein anchors, have been proposed to play a role during T-cell activation. The MVB2 cell line is a mutant, derived from the wild-type T-T hybrid YH.16.33, which has a defect in the biosynthesis of PtdIns-protein linkages. As a consequence, MVB2 mutants are defective in activation through the T-cell receptor. Despite the lack of glycosyl-PtdIns anchors in the mutant MVB2 cells, a comparison of the levels and structural features of the insulin-sensitive glycosyl-PtdIns between the MVB2 and YH.16.33 lineages indicates that both cell lines are identical in this respect. The time course for insulin-responsiveness coincides in both cell lines, with maximal hydrolysis 30 s after insulin addition. The ultimate localization of insulin-regulated glycosyl-PtdIns at the outer surface of the cell membrane is also similar. These data indicate that the glycosyl-PtdIns whose hydrolysis is regulated by insulin is not anchoring proteins at the cell surface of T-lymphocytes.

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