Author response: Tissue-specific shaping of the TCR repertoire and antigen specificity of iNKT cells

Tissue homeostasis is critically dependent on the function of tissue-resident lymphocytes, including lipid-reactive invariant natural killer T (iNKT) cells. Yet, if and how the tissue environment shapes the antigen specificity of iNKT cells remains unknown. By analysing iNKT cells from lymphoid tissues of mice and humans we demonstrate that their T cell receptor (TCR) repertoire is highly diverse and is distinct for cells from various tissues resulting in differential lipid-antigen recognition. Within peripheral tissues iNKT cell recent thymic emigrants exhibit a different TCR repertoire than mature cells, suggesting that the iNKT population is shaped after arrival to the periphery. Consistent with this, iNKT cells from different organs show distinct basal activation, proliferation and clonal expansion. Moreover, the iNKT cell TCR repertoire changes following immunisation and is shaped by age and environmental changes. Thus, post-thymic modification of the TCR-repertoire underpins the distinct antigen specificity for iNKT cells in peripheral tissues

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Author response for "iNKT cells with high PLZF expression are recruited into the lung via CCL21‐CCR7 signaling to facilitate the development of asthma tolerance in mice"

10.1002/eji.202048798/v3/response1 ◽

2020 ◽

Author(s):

Xintong Feng ◽

Caiqi Zhao ◽

Ling Li ◽

Jingjing Feng ◽

Wei He ◽

...

Keyword(s):

Author Response ◽

Inkt Cells

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Author response for "Tissue specific production of MicroRNA‐155 inhibits melanocortin 5 receptor dependent suppressor macrophages to promote experimental autoimmune uveitis"

10.1002/eji.201848073/v2/response1 ◽

2019 ◽

Author(s):

Fauziyya Muhammad ◽

Anna Trivett ◽

Dawei Wang ◽

Darren J. Lee

Keyword(s):

Author Response ◽

Specific Production ◽

Experimental Autoimmune Uveitis ◽

Tissue Specific ◽

Autoimmune Uveitis ◽

Experimental Autoimmune

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Author response for "Murine iNKT cells are depleted by liver damage via activation of P2RX7"

10.1002/eji.201948509/v2/response1 ◽

2020 ◽

Author(s):

Astrid A. Bovens ◽

Thomas H. Wesselink ◽

Felix M. Behr ◽

Natasja A. M. Kragten ◽

René A. W. Lier ◽

...

Keyword(s):

Liver Damage ◽

Author Response ◽

Inkt Cells

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Probing T-cell response by sequence-based probabilistic modeling

10.1101/2020.12.17.423283 ◽

2020 ◽

Author(s):

Barbara Bravi ◽

Vinod P. Balachandran ◽

Benjamin D. Greenbaum ◽

Aleksandra M. Walczak ◽

Thierry Mora ◽

...

Keyword(s):

T Cell ◽

Probabilistic Models ◽

Cell Receptor ◽

T Cell Response ◽

Specific Response ◽

Sequence Motifs ◽

Antigen Specificity ◽

Human T Cell ◽

Machine Learning Approach ◽

Tcr Repertoire

AbstractWith the increasing ability to use high-throughput next-generation sequencing to quantify the diversity of the human T cell receptor (TCR) repertoire, the ability to use TCR sequences to infer antigen-specificity could greatly aid potential diagnostics and therapeutics. Here, we use a machine-learning approach known as Restricted Boltzmann Machine to develop a sequence-based inference approach to identify antigen-specific TCRs. Our approach combines probabilistic models of TCR sequences with clone abundance information to extract TCR sequence motifs central to an antigen-specific response. We use this model to identify patient personalized TCR motifs that respond to individual tumor and infectious disease antigens, and to accurately discriminate specific from non-specific responses. Furthermore, the hidden structure of the model results in an interpretable representation space where TCRs responding to the same antigen cluster, correctly discriminating the response of TCR to different viral epitopes. The model can therefore be used to identify both experimental and condition specific responding TCRs, of great importance to advancing personalized immunotherapies.

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A Framework to Identify Antigen-Expanded T Cell Receptor Clusters Within Complex Repertoires

Frontiers in Immunology ◽

10.3389/fimmu.2021.735584 ◽

2021 ◽

Vol 12 ◽

Author(s):

Valentina Ceglia ◽

Erin J. Kelley ◽

Annalee S. Boyle ◽

Sandra Zurawski ◽

Heather L. Mead ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

T Cell Responses ◽

Cell Receptor ◽

Antigen Specificity ◽

Protein Antigens ◽

Cell Responses ◽

Tcr Repertoire ◽

Receptor Clusters ◽

Theoretical Sensitivity

Common approaches for monitoring T cell responses are limited in their multiplexity and sensitivity. In contrast, deep sequencing of the T Cell Receptor (TCR) repertoire provides a global view that is limited only in terms of theoretical sensitivity due to the depth of available sampling; however, the assignment of antigen specificities within TCR repertoires has become a bottleneck. This study combines antigen-driven expansion, deep TCR sequencing, and a novel analysis framework to show that homologous ‘Clusters of Expanded TCRs (CETs)’ can be confidently identified without cell isolation, and assigned to antigen against a background of non-specific clones. We show that clonotypes within each CET respond to the same epitope, and that protein antigens stimulate multiple CETs reactive to constituent peptides. Finally, we demonstrate the personalized assignment of antigen-specificity to rare clones within fully-diverse uncultured repertoires. The method presented here may be used to monitor T cell responses to vaccination and immunotherapy with high fidelity.

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