A molecular basis for the T cell response in HLA-DQ2.2 mediated celiac disease

The highly homologous human leukocyte antigen (HLA)-DQ2 molecules, HLA-DQ2.5 and HLA-DQ2.2, are implicated in the pathogenesis of celiac disease (CeD) by presenting gluten peptides to CD4+ T cells. However, while HLA-DQ2.5 is strongly associated with disease, HLA-DQ2.2 is not, and the molecular basis underpinning this differential disease association is unresolved. We here provide structural evidence for how the single polymorphic residue (HLA-DQ2.5-Tyr22α and HLA-DQ2.2-Phe22α) accounts for HLA-DQ2.2 additionally requiring gluten epitopes possessing a serine at the P3 position of the peptide. In marked contrast to the biased T cell receptor (TCR) usage associated with HLA-DQ2.5–mediated CeD, we demonstrate with extensive single-cell sequencing that a diverse TCR repertoire enables recognition of the immunodominant HLA-DQ2.2-glut-L1 epitope. The crystal structure of two CeD patient-derived TCR in complex with HLA-DQ2.2 and DQ2.2-glut-L1 (PFSEQEQPV) revealed a docking strategy, and associated interatomic contacts, which was notably distinct from the structures of the TCR:HLA-DQ2.5:gliadin epitope complexes. Accordingly, while the molecular surfaces of the antigen-binding clefts of HLA-DQ2.5 and HLA-DQ2.2 are very similar, differences in the nature of the peptides presented translates to differences in responding T cell repertoires and the nature of engagement of the respective antigen-presenting molecules, which ultimately is associated with differing disease penetrance.

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Biased T Cell Receptor Usage Directed against Human Leukocyte Antigen DQ8-Restricted Gliadin Peptides Is Associated with Celiac Disease

Immunity ◽

10.1016/j.immuni.2012.07.013 ◽

2012 ◽

Vol 37 (4) ◽

pp. 611-621 ◽

Cited By ~ 80

Author(s):

Sophie E. Broughton ◽

Jan Petersen ◽

Alex Theodossis ◽

Stephen W. Scally ◽

Khai Lee Loh ◽

...

Keyword(s):

Celiac Disease ◽

T Cell ◽

Human Leukocyte Antigen ◽

T Cell Receptor ◽

Human Leukocyte ◽

Cell Receptor ◽

Leukocyte Antigen ◽

Receptor Usage ◽

Gliadin Peptides

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Faculty Opinions recommendation of A major histocompatibility complex-peptide-restricted antibody and t cell receptor molecules recognize their target by distinct binding modes: crystal structure of human leukocyte antigen (HLA)-A1-MAGE-A1 in complex with FAB-HYB3.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1022327.251780 ◽

2004 ◽

Author(s):

David Margulies

Keyword(s):

Crystal Structure ◽

Major Histocompatibility Complex ◽

T Cell ◽

Human Leukocyte Antigen ◽

T Cell Receptor ◽

Human Leukocyte ◽

Cell Receptor ◽

Binding Modes ◽

Leukocyte Antigen ◽

Histocompatibility Complex

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Human Leukocyte Antigen-Class I Alleles and the Autoreactive T Cell Response in Psoriasis Pathogenesis

Frontiers in Immunology ◽

10.3389/fimmu.2018.00954 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 19

Author(s):

Jörg Christoph Prinz

Keyword(s):

T Cell ◽

Human Leukocyte Antigen ◽

Cell Response ◽

Human Leukocyte Antigen Class ◽

Human Leukocyte ◽

T Cell Response ◽

Class I ◽

Leukocyte Antigen ◽

Autoreactive T Cell ◽

Leukocyte Antigen Class I

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Differential expression of predisposing HLA-DQ2.5 alleles in DR5/DR7 celiac disease patients affects the pathological immune response to gluten

Scientific Reports ◽

10.1038/s41598-020-73907-2 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Laura Pisapia ◽

Stefania Picascia ◽

Federica Farina ◽

Pasquale Barba ◽

Carmen Gianfrani ◽

...

Keyword(s):

Celiac Disease ◽

T Cell ◽

Differential Expression ◽

T Cell Activation ◽

Cell Response ◽

Cell Activation ◽

T Cell Response ◽

Risk Alleles ◽

Personalized Diagnosis ◽

Antigen Presenting

Abstract The DR5-DQ7/DR7-DQ2 genotype is very frequent among patients affected by celiac disease (CD), in Europe. This genotype, associated to high risk of CD, carries the HLA-DQA1*05 and HLA-DQB1*02 predisposing alleles, in trans configuration. The alleles encode the DQ2.5 heterodimer responsible of gluten peptide presentation on the surface of antigen-presenting cells (APCs), and consequent pathogenic CD4+ T cell activation. We demonstrated that DR5/DR7 APCs induce an anti-gluten CD4+ T cell response, of comparable intensity to that observed with APCs carrying DR1/DR3 genotype, which risk alleles are in cis configuration. In addition, we showed that DR5/DR7 APCs from celiac patients stimulated an effector CD4+ T cell response higher with respect to that induced by DR5/DR7 APCs from healthy subjects. To explain these findings, we assessed the DQ2.5 RNA and protein quantity. We showed that the expression of DQA1*05 and DQB1*02 risk alleles is much higher than the expression of non-CD-associated alleles, in agreement with the previous results obtained with DR1/DR3 genotype. The differential expression of transcripts influences the quantity of DQα1*05 and DQβ1*02 chains and, as consequence, the cell surface density of DQ2.5 heterodimers. Moreover, both RNA and proteins, are more abundant in APCs from celiac patients than controls. Finally, to unravel the mechanism regulating the expression of predisposing DQA1*05 and DQB1*02 alleles, we quantified the new synthetized RNA and found that the differential expression is explained by their transcription rate. Our results confirmed that the strength of antigen-specific CD4+ T cell response is mainly determined by the amount of gluten in the diet and provided a new possible approach for a personalized diagnosis and for risk stratification.

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Class II human leukocyte antigen genes and T cell receptor polymorphisms in patients with rheumatoid arthritis

The American Journal of Medicine ◽

10.1016/0002-9343(88)90373-7 ◽

1988 ◽

Vol 85 (6) ◽

pp. 14-16 ◽

Cited By ~ 31

Author(s):

Xiaojiang Gao ◽

Edward J. Ball ◽

Lori Dombrausky ◽

Nancy J. Olsen ◽

Theodore Pincus ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cell ◽

Human Leukocyte Antigen ◽

T Cell Receptor ◽

Human Leukocyte ◽

Cell Receptor ◽

Class Ii ◽

Leukocyte Antigen

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Interleukin-15 redirects the outcome of a tolerizing T-cell stimulus from apoptosis to anergy

Blood ◽

10.1182/blood.v96.3.1006.015k27_1006_1012 ◽

2000 ◽

Vol 96 (3) ◽

pp. 1006-1012 ◽

Cited By ~ 1

Author(s):

Hans Dooms ◽

Tom Van Belle ◽

Marjory Desmedt ◽

Pieter Rottiers ◽

Johan Grooten

Keyword(s):

T Cell ◽

Cell Receptor ◽

T Cell Response ◽

Peripheral Tolerance ◽

Clonal Deletion ◽

Cell Clones ◽

Receptor Signal ◽

Cytokine Milieu ◽

Antigen Presenting

Clonal deletion and anergy are 2 mechanisms used by the immune system to establish peripheral tolerance. In vitro, these mechanisms are induced in T lymphocytes by triggering the T-cell receptor (signal 1) in the absence of costimulation (signal 2). T-cell clones have been shown either to become anergic or to die in response to signal 1 alone; yet the factors that govern this choice remain unknown. This study evaluated the influence of the cytokines interleukin (IL)-2 and IL-15 on the response of the Th1 clone hemagglutinin (T-HA) to signal 1, delivered by stimulation with immobilized anti-CD3 monoclonal antibody (mAb). The response induced by immobilized anti-CD3 mAb was dependent on the cytokine milieu; in the presence of IL-2, T-HA cells were subject to apoptosis, whereas in the presence of IL-15 the cells remained viable but showed proliferative unresponsiveness. After release from the anti-CD3 stimulus, the IL-15-rescued T-HA cells regained responsiveness to IL-2 and IL-15 growth factor activity. However, they were unable to proliferate when stimulated with their cognate antigen presented by professional antigen-presenting cells (signal 1 plus 2) and thus had acquired an anergic phenotype. These data assign a novel function to the previously reported antiapoptotic activity of IL-15, namely, the capacity to redirect the T-cell response to partial stimulation from clonal deletion to anergy. Furthermore, they emphasize that the cytokine environment can critically influence the outcome of a tolerizing stimulus.

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Modulation of Tumor Immunity by Soluble and Membrane-Bound Molecules at the Immunological Synapse

Clinical and Developmental Immunology ◽

10.1155/2013/450291 ◽

2013 ◽

Vol 2013 ◽

pp. 1-19 ◽

Cited By ~ 7

Author(s):

Pablo A. González ◽

Leandro J. Carreño ◽

Pablo F. Céspedes ◽

Susan M. Bueno ◽

Claudia A. Riedel ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immunological Synapse ◽

Recent Literature ◽

Cell Receptor ◽

T Cell Response ◽

Host Immune System ◽

Potentially Malignant ◽

Membrane Bound ◽

Antigen Presenting

To circumvent pathology caused by infectious microbes and tumor growth, the host immune system must constantly clear harmful microorganisms and potentially malignant transformed cells. This task is accomplished in part by T-cells, which can directly kill infected or tumorigenic cells. A crucial event determining the recognition and elimination of detrimental cells is antigen recognition by the T cell receptor (TCR) expressed on the surface of T cells. Upon binding of the TCR to cognate peptide-MHC complexes presented on the surface of antigen presenting cells (APCs), a specialized supramolecular structure known as the immunological synapse (IS) assembles at the T cell-APC interface. Such a structure involves massive redistribution of membrane proteins, including TCR/pMHC complexes, modulatory receptor pairs, and adhesion molecules. Furthermore, assembly of the immunological synapse leads to intracellular events that modulate and define the magnitude and characteristics of the T cell response. Here, we discuss recent literature on the regulation and assembly of IS and the mechanisms evolved by tumors to modulate its function to escape T cell cytotoxicity, as well as novel strategies targeting the IS for therapy.

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A subset of HLA-I peptides are not genomically templated: Evidence for cis- and trans-spliced peptide ligands

Science Immunology ◽

10.1126/sciimmunol.aar3947 ◽

2018 ◽

Vol 3 (28) ◽

pp. eaar3947 ◽

Cited By ~ 53

Author(s):

Pouya Faridi ◽

Chen Li ◽

Sri H. Ramarathinam ◽

Julian P. Vivian ◽

Patricia T. Illing ◽

...

Keyword(s):

T Cell ◽

Posttranslational Modifications ◽

Human Leukocyte ◽

Cell Receptor ◽

Peptide Fragments ◽

Leukocyte Antigen ◽

Cell Immunity ◽

Probable Outcome ◽

Hla Binding ◽

Cis And Trans

The diversity of peptides displayed by class I human leukocyte antigen (HLA) plays an essential role in T cell immunity. The peptide repertoire is extended by various posttranslational modifications, including proteasomal splicing of peptide fragments from distinct regions of an antigen to form nongenomically templated cis-spliced sequences. Previously, it has been suggested that a fraction of the immunopeptidome constitutes such cis-spliced peptides; however, because of computational limitations, it has not been possible to assess whether trans-spliced peptides (i.e., the fusion of peptide segments from distinct antigens) are also bound and presented by HLA molecules, and if so, in what proportion. Here, we have developed and applied a bioinformatic workflow and demonstrated that trans-spliced peptides are presented by HLA-I, and their abundance challenges current models of proteasomal splicing that predict cis-splicing as the most probable outcome. These trans-spliced peptides display canonical HLA-binding sequence features and are as frequently identified as cis-spliced peptides found bound to a number of different HLA-A and HLA-B allotypes. Structural analysis reveals that the junction between spliced peptides is highly solvent exposed and likely to participate in T cell receptor interactions. These results highlight the unanticipated diversity of the immunopeptidome and have important implications for autoimmunity, vaccine design, and immunotherapy.

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CD86+ or HLA-G+ can be transferred via trogocytosis from myeloma cells to T cells and are associated with poor prognosis

Blood ◽

10.1182/blood-2012-03-416792 ◽

2012 ◽

Vol 120 (10) ◽

pp. 2055-2063 ◽

Cited By ~ 52

Author(s):

Ross Brown ◽

Karieshma Kabani ◽

James Favaloro ◽

Shihong Yang ◽

P. Joy Ho ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Poor Prognosis ◽

Plasma Cells ◽

Side Population ◽

Immune Surveillance ◽

Human Leukocyte ◽

Cell Receptor ◽

Lymphocytic Leukemia ◽

Leukocyte Antigen

Abstract The transfer of membrane proteins between cells during contact, known as trogocytosis, can create novel cells with a unique phenotype and altered function. We demonstrate that trogocytosis is more common in multiple myeloma (MM) than chronic lymphocytic leukemia and Waldenstrom macroglobulinaemia; that T cells are more probable to be recipients than B or natural killer cells; that trogocytosis occurs independently of either the T-cell receptor or HLA compatibility; and that after trogocytosis, T cells with acquired antigens can become novel regulators of T-cell proliferation. We screened 168 patients with MM and found that CD86 and human leukocyte antigen G (HLA-G) were antigens commonly acquired by T cells from malignant plasma cells. CD3+CD86acq+ and CD3+ HLA-Gacq+ cells were more prevalent in bone marrow than peripheral blood samples. The presence of either CD86 or HLA-G on malignant plasma cells was associated with a poor prognosis. CD38++ side population cells expressed HLA-G, suggesting that these putative myeloma stem cells could generate immune tolerance. HLA-G+ T cells had a regulatory potency similar to natural Tregs, thus providing another novel mechanism for MM to avoid effective immune surveillance.

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