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

2018 ◽  
Vol 3 (28) ◽  
pp. eaar3947 ◽  
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.

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

Immunity ◽  
2012 ◽  
Vol 37 (4) ◽  
pp. 611-621 ◽  
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

scholarly journals Comparative analysis of predicted HLA binding of immunoglobulin idiotype sequences indicates T cell–mediated immunosurveillance in follicular lymphoma

Blood ◽  
2010 ◽  
Vol 116 (10) ◽  
pp. 1734-1736 ◽  
Author(s):  
Anna-Maria Strothmeyer ◽  
Dimitrios Papaioannou ◽  
Marcus Dühren-von Minden ◽  
Marcelo Navarrete ◽  
Katja Zirlik ◽  
...  
Keyword(s):  
T Cell ◽  
Follicular Lymphoma ◽  
Somatic Hypermutation ◽  
Human Leukocyte ◽  
Active Immunization ◽  
Cell Immunity ◽  
Complementarity Determining Regions ◽  
Hla Binding ◽  
Sum Scores

AbstractActive immunization with the idiotype of follicular lymphoma induces tumor-specific immunity. T cells induced in vivo by idiotype vaccination recognize human leukocyte antigen (HLA)–restricted hypervariable but not conserved idiotype peptides. We hypothesized that idiotype-directed T-cell immunity occurs naturally and performed a reverse immunology analysis of idiotype HLA binding in 39 follicular lymphoma patients. For every idiotype, the sum of HLA-A or -B binding scores of the 20 highest-scoring peptides was calculated for all 39 HLA types through the BIMAS algorithm. The idiotype sum score of every patient's lymphoma was compared on the respective patient's HLA type to the mean of the sum scores of the remaining 38 idiotypes. Autologous idiotypes had lower immunogenicity than allogeneic idiotypes. Dif ferential immunogenicity resided predominantly in all 3 complementarity-determining regions rather than in framework peptides. Idiotype immunogenicity was not changed by somatic hypermutation. These findings indicate T cell–mediated immunosurveillance of follicular lymphoma directed specifically against individual idiotype epitopes.

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

1988 ◽  
Vol 85 (6) ◽  
pp. 14-16 ◽  
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

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

2020 ◽  
Vol 117 (6) ◽  
pp. 3063-3073 ◽  
Author(s):  
Yi Tian Ting ◽  
Shiva Dahal-Koirala ◽  
Hui Shi Keshia Kim ◽  
Shuo-Wang Qiao ◽  
Ralf S. Neumann ◽  
...  
Keyword(s):  
Celiac Disease ◽  
T Cell ◽  
Molecular Basis ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
T Cell Response ◽  
Leukocyte Antigen ◽  
Disease Penetrance ◽  
Polymorphic Residue ◽  
Antigen Presenting

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.

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

Blood ◽  
2012 ◽  
Vol 120 (10) ◽  
pp. 2055-2063 ◽  
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.

scholarly journals 200. Generation of CAR-T Cells Lacking T Cell Receptor and Human Leukocyte Antigen Using Engineered Meganucleases

2016 ◽  
Vol 24 ◽  
pp. S78 ◽  
Author(s):  
Christina Pham ◽  
Aaron Martin ◽  
Jeyaraj Antony ◽  
Daniel MacLeod ◽  
Audrey Brown ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Leukocyte Antigen ◽  
T Cell Receptor ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
Leukocyte Antigen ◽  
Car T Cells ◽  
Car T

Redirected T Cell Cytotoxicity in Cancer Therapy

2019 ◽  
Vol 70 (1) ◽  
pp. 437-450 ◽  
Author(s):  
Raphael A. Clynes ◽  
John R. Desjarlais
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
Cross Linking ◽  
Receptor Complex ◽  
Leukocyte Antigen ◽  
Tumor Associated Antigen ◽  
Tumor Cell Killing ◽  
T Cell Cytotoxicity

Bispecific antibodies that recruit and redirect T cells to attack tumor cells have tremendous potential for the treatment of various malignancies. In general, this class of therapeutics, known as CD3 bispecifics, promotes tumor cell killing by cross-linking a CD3 component of the T cell receptor complex with a tumor-associated antigen on the surface of the target cell. Importantly, this mechanism does not rely on a cognate interaction between the T cell receptor and a peptide:HLA complex, thereby circumventing HLA (human leukocyte antigen) restriction. Hence, CD3 bispecifics may find a key role in addressing tumors with low neoantigen content and/or low inflammation, and this class of therapeutics may productively combine with checkpoint blockade. A wide array of formats and optimization approaches has been developed, and a wave of CD3 bispecifics is proceeding into human clinical trials for a range of indications, with promising signs of therapeutic activity.

scholarly journals T cell receptor V-segment frequencies in peripheral blood T cells correlate with human leukocyte antigen type.

1991 ◽  
Vol 174 (5) ◽  
pp. 1139-1146 ◽  
Author(s):  
B Gulwani-Akolkar ◽  
D N Posnett ◽  
C H Janson ◽  
J Grunewald ◽  
H Wigzell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Leukocyte Antigen ◽  
T Cell Receptor ◽  
Peripheral Blood ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
Class I ◽  
Sibling Pairs ◽  
Leukocyte Antigen

We compared T cell receptor (TCR) V-segment frequencies in human leukocyte antigen (HLA) identical siblings to sibling pairs who differ at one or both HLA haplotypes using four V beta-specific and one V alpha-specific monoclonal antibody. In every one of nine families HLA-identical sibs had the most similar patterns of V-segment frequencies in their peripheral blood, whereas totally mismatched sibs were, in general, the most dissimilar; HLA haploidentical sibs tended to be intermediate between the two groups. The degree of similarity among HLA-identical sibs was comparable to that observed among three pairs of identical twins suggesting that HLA is the major genetic component influencing TCR V-segment frequency. Consistent with this observation, it was found that the frequency of T cells expressing particular V beta segments was skewed towards either CD4+ or CD8+ cells indicating that T cells expressing some V beta genes may be positively selected primarily by class I or class II major histocompatibility complex proteins. Finally, it was observed that individuals who express the HLA class I specificity, B38, tend to express high levels of V alpha 2.3+ cells among their CD8+ T cells. These observations represent definitive proof that human V-segment frequencies are profoundly influenced by the HLA complex.

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