Structural Basis of Specificity and Cross-Reactivity in T Cell Receptors Specific for Cytochrome c–I-Ek

HIV controllers (HCs) are individuals who can naturally control HIV infection, partially due to potent HIV-specific CD8+ T cell responses. Here, we examined the hypothesis that superior function of CD8+ T cells from HCs is encoded by their T cell receptors (TCRs). We compared the functional properties of immunodominant HIV-specific TCRs obtained from HLA-B*2705 HCs and chronic progressors (CPs) following expression in primary T cells. T cells transduced with TCRs from HCs and CPs showed equivalent induction of epitope-specific cytotoxicity, cytokine secretion, and antigen-binding properties. Transduced T cells comparably, albeit modestly, also suppressed HIV infection in vitro and in humanized mice. We also performed extensive molecular dynamics simulations that provided a structural basis for similarities in cytotoxicity and epitope cross-reactivity. These results demonstrate that the differential abilities of HIV-specific CD8+ T cells from HCs and CPs are not genetically encoded in the TCRs alone and must depend on additional factors.

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Predicting Cross-Reactivity and Antigen Specificity of T Cell Receptors

Frontiers in Immunology ◽

10.3389/fimmu.2020.565096 ◽

2020 ◽

Vol 11 ◽

Cited By ~ 1

Author(s):

Chloe H. Lee ◽

Mariolina Salio ◽

Giorgio Napolitani ◽

Graham Ogg ◽

Alison Simmons ◽

...

Keyword(s):

T Cell ◽

T Cell Receptors ◽

Cross Reactivity ◽

Antigen Specificity ◽

Cell Receptors

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T-cell Receptors Engineered De Novo for Peptide Specificity Can Mediate Optimal T-cell Activity without Self Cross-Reactivity

Cancer Immunology Research ◽

10.1158/2326-6066.cir-19-0035 ◽

2019 ◽

Vol 7 (12) ◽

pp. 2025-2035 ◽

Cited By ~ 4

Author(s):

Preeti Sharma ◽

Daniel T. Harris ◽

Jennifer D. Stone ◽

David M. Kranz

Keyword(s):

T Cell ◽

T Cell Receptors ◽

De Novo ◽

Cell Activity ◽

Cross Reactivity ◽

Cell Receptors ◽

Peptide Specificity

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Predominant use of a Vα gene segment in mouse T-cell receptors for cytochrome c

Nature ◽

10.1038/324679a0 ◽

1986 ◽

Vol 324 (6098) ◽

pp. 679-682 ◽

Cited By ~ 123

Author(s):

Astar Winoto ◽

James L. Urban ◽

Nancy C. Lan ◽

Joan Goverman ◽

Leroy Hood ◽

...

Keyword(s):

T Cell ◽

Cytochrome C ◽

T Cell Receptors ◽

Gene Segment ◽

Cell Receptors

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The somatically generated portion of T cell receptor CDR3α contributes to the MHC allele specificity of the T cell receptor

eLife ◽

10.7554/elife.30918 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 12

Author(s):

Philippa Marrack ◽

Sai Harsha Krovi ◽

Daniel Silberman ◽

Janice White ◽

Eleanor Kushnir ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

T Cell ◽

Positive Selection ◽

T Cell Receptor ◽

T Cell Receptors ◽

Cell Receptor ◽

Structural Basis ◽

Major Histocompatibility ◽

Cell Receptors ◽

Histocompatibility Complex

Mature T cells bearing αβ T cell receptors react with foreign antigens bound to alleles of major histocompatibility complex proteins (MHC) that they were exposed to during their development in the thymus, a phenomenon known as positive selection. The structural basis for positive selection has long been debated. Here, using mice expressing one of two different T cell receptor β chains and various MHC alleles, we show that positive selection-induced MHC bias of T cell receptors is affected both by the germline encoded elements of the T cell receptor α and β chain and, surprisingly, dramatically affected by the non germ line encoded portions of CDR3 of the T cell receptor α chain. Thus, in addition to determining specificity for antigen, the non germline encoded elements of T cell receptors may help the proteins cope with the extremely polymorphic nature of major histocompatibility complex products within the species.

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Analysis of SARS-CoV-2 specific T-cell receptors in ImmuneCode reveals cross-reactivity to immunodominant Influenza M1 epitope

10.1101/2020.06.20.160499 ◽

2020 ◽

Cited By ~ 4

Author(s):

John-William Sidhom ◽

Alexander S. Baras

Keyword(s):

T Cell ◽

T Cell Receptor ◽

T Cell Receptors ◽

Cell Receptor ◽

Cross Reactivity ◽

Cell Receptors

Adaptive Biotechnologies and Microsoft have recently partnered to release ImmuneCode, a database containing SARS-CoV-2 specific T-cell receptors derived through MIRA, a T-cell receptor (TCR) sequencing based sequencing approach to identify antigen-specific TCRs. Herein, we query the extent of cross reactivity between these derived SARS-CoV-2 specific TCRs and other known antigens present in McPas-TCR, a manually curated catalogue of pathology-associated TCRs. We reveal cross reactivity between SARS-CoV-2 specific TCRs and the immunodominant Influenza GILGFVFTL M1 epitope, suggesting the importance of further work in characterizing the implications of prior Influenza exposure or co-exposure to the pathology of SARS-CoV-2 illness.

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A Structural Basis for the Selection of Dominant αβ T Cell Receptors in Antiviral Immunity

Immunity ◽

10.1016/s1074-7613(02)00513-7 ◽

2003 ◽

Vol 18 (1) ◽

pp. 53-64 ◽

Cited By ~ 267

Author(s):

Lars Kjer-Nielsen ◽

Craig S. Clements ◽

Anthony W. Purcell ◽

Andrew G. Brooks ◽

James C. Whisstock ◽

...

Keyword(s):

T Cell ◽

T Cell Receptors ◽

Antiviral Immunity ◽

Structural Basis ◽

Cell Receptors ◽

Selection Of

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Facile method for screening clinical T cell receptors for off-target peptide-HLA reactivity

10.1101/472480 ◽

2018 ◽

Cited By ~ 1

Author(s):

Marvin H. Gee ◽

Xinbo Yang ◽

K. Christopher Garcia

Keyword(s):

T Cell ◽

T Cell Receptors ◽

Human Leukocyte ◽

Cross Reactivity ◽

Affinity Maturation ◽

Yeast Display ◽

Cell Therapies ◽

Cell Receptors ◽

Leukocyte Antigen ◽

Clinical Toxicity

ABSTRACTT cell receptors (TCRs) exhibit varying degrees of cross-reactivity for peptides presented by the human leukocyte antigen (HLA). In engineered T cell therapies, TCR affinity maturation is a strategy to improve the sensitivity and potency to often a low-density peptide-HLA (pHLA) target. However, the process of affinity maturation towards a known pHLA complex can introduce new and untoward cross-reactivities that are difficult to detect and raises significant safety concerns. We developed a yeast-display platform of pHLA consisting of ~100 million different 9mer peptides presented by HLA-A*01 and used a previously established selection approach to validate the specificity and cross-reactivity of the A3A TCR, an affinity-matured TCR against the MAGE-A3 target (EVDPIGHLY). We were able to identify reactivity against the titin peptide (ESDPIVAQY), to which there is now known clinical toxicity. We propose the use of yeast-display of pHLA libraries to determine cross-reactive profiles of candidate clinical TCRs to ensure safety and pHLA specificity of natural and affinity-matured TCRs.

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SARS-CoV-2 epitopes are recognized by a public and diverse repertoire of human T-cell receptors

10.1101/2020.05.20.20107813 ◽

2020 ◽

Cited By ~ 8

Author(s):

Alina S. Shomuradova ◽

Murad S. Vagida ◽

Savely A. Sheetikov ◽

Ksenia V. Zornikova ◽

Dmitry Kiryukhin ◽

...

Keyword(s):

T Cell ◽

T Cell Receptors ◽

Cell Response ◽

Adaptive Immune Response ◽

Cross Reactivity ◽

T Cell Response ◽

Cell Reactivity ◽

Cell Receptors ◽

Human T Cell ◽

Healthy Donors

SummaryUnderstanding the hallmarks of the adaptive immune response to SARS-CoV-2 is critical for fighting the COVID-19 pandemic. We assessed the antibody and T-cell reactivity in COVID-19 convalescent patients and healthy donors sampled both prior to and during the pandemic. The numbers of SARS-CoV-2-specific T cells were increased in healthy donors examined during COVID-19. Combined with the absence of symptoms and humoral response across that group, this finding suggests that some individuals might be protected by T-cell cross-reactivity. In convalescent patients we observed public and diverse T-cell response to SARS-CoV-2 epitopes, revealing T-cell receptor motifs with germline-encoded features. Bulk CD4+ and CD8+ T-cell responses to Spike glycoprotein were mediated by groups of homologous T-cell receptors, some of them shared across multiple donors. Overall, our results demonstrate that T-cell response to SARS-CoV-2, including the identified set of specific T-cell receptors, can serve as a useful biomarker for surveying viral exposure and immunity.

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Identification of Cross-Reactive CD8+ T Cell Receptors with High Functional Avidity to a SARS-CoV-2 Immunodominant Epitope and Its Natural Mutant Variants

10.1101/2020.11.02.364729 ◽

2020 ◽

Cited By ~ 1

Author(s):

Chao Hu ◽

Meiying Shen ◽

Xiaojian Han ◽

Qian Chen ◽

Luo Li ◽

...

Keyword(s):

T Cell ◽

T Cell Receptors ◽

Vaccine Development ◽

Ex Vivo ◽

T Cell Responses ◽

Cross Reactivity ◽

Functional Avidity ◽

Cell Receptors ◽

Cell Functions ◽

Cell Responses

ABSTRACTDespite the growing knowledge of T cell responses and their epitopes in COVID-19 patients, there is a lack of detailed characterizations for T cell-antigen interactions and T cell functions. Using a peptide library predicted with HLA class I-restriction, specific CD8+ T cell responses were identified in over 75% of COVID-19 convalescent patients. Among the 15 SARS-CoV-2 epitopes identified from the S and N proteins, N361-369 (KTFPPTEPK) was the most dominant epitope. Importantly, we discovered 2 N361-369-specific T cell receptors (TCRs) with high functional avidity, and they exhibited complementary cross-reactivity to reported N361-369 mutant variants. In dendritic cells (DCs) and the lung organoid model, we found that the N361-369 epitope could be processed and endogenously presented to elicit the activation and cytotoxicity of CD8+ T cells ex vivo. Our study evidenced potential mechanisms of cellular immunity to SARS-CoV-2, illuminating natural ways of viral clearance with high relevancy in the vaccine development.

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