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A class-mismatched TCR bypasses MHC restriction via an unorthodox but fully functional binding geometry
MHC restriction depicts CD4+ T cell activation by MHC-II and CD8A+ by MHC-I, but rare T cells with mismatched MHC restriction have been reported. Here the authors use crystallography to describe features of such a mismatched TCR-MHC interaction and implicate an atypical TCR structure and TCR-MHC interface as contributing factors.
- Nishant K. Singh
- , Jesus A. Alonso
- & Brian M. Baker
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| Open Access
Discriminating cross-reactivity in polyclonal IgG1 responses against SARS-CoV-2 variants of concern
Profiling antibody repertoires using proteomic approaches may provide a way of screening for antibody cross-reactivity against SARS-CoV-2 variants. Here the authors use a IgG1 specific cleavage method to analyse the IgG1 repertoire within recovered patients and relate this to antibody binding and neutralisation.
- Danique M. H. van Rijswijck
- , Albert Bondt
- & Albert J. R. Heck
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| Open Access
Covalent TCR-peptide-MHC interactions induce T cell activation and redirect T cell fate in the thymus
Differentiation and activation of T cells are normally modulated by non-covalent interactions between T cell receptor (TCR) and antigenic peptides. Here the authors use step-wise mutations, biochemical characterization and structural insights to describe the contributions of natural covalent bonds between TCR and antigenic peptides during these processes.
- Christopher Szeto
- , Pirooz Zareie
- & Stephen R. Daley
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| Open Access
Indispensable epigenetic control of thymic epithelial cell development and function by polycomb repressive complex 2
Development of the T cells requires functions from thymic epithelial cells, whose development and function are epigenetically regulated. Here the authors show that inactivation of the polycomb repressive complex 2 (PRC2) alters the H3K27me3 configuration, reduces TEC functions, reveals a specific TEC subset, and hampers T cell development.
- Thomas Barthlott
- , Adam E. Handel
- & Georg A. Holländer
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| Open Access
Diversity in medullary thymic epithelial cells controls the activity and availability of iNKT cells
Thymus is a unique environment hosting the development of many T cell subsets with distinct functions. Here the authors show that medullary thymic epithelial cells (mTEC) are functionally diverse, with LTβR signaling serving differential regulation of mTEC for specific control of multiple lineages of invariant natural killer T cells.
- Beth Lucas
- , Andrea J. White
- & Graham Anderson
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Article
| Open Access
Clonal kinetics and single-cell transcriptional profiling of CAR-T cells in patients undergoing CD19 CAR-T immunotherapy
Understanding factors that impact CAR T cell expansion in the clinic is crucial to improving its therapeutic success. Here the authors document heterogeneity in the clonal dynamics of CAR-T cells by tracking individual clones using the endogenous TCR and integration sites and provide further insights into the role of transcriptional states in clonal kinetics.
- Alyssa Sheih
- , Valentin Voillet
- & Cameron J. Turtle
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| Open Access
Identification of drug-specific public TCR driving severe cutaneous adverse reactions
Severe cutaneous adverse reactions (SCAR) is a T cell-mediated, potentially lethal drug hypersensitivity (DH). Here, the authors identify a carbamazepine-specific TCR common among patients with carbamazepine-induced SCAR that confers SCAR-like pathology in mice upon carbamazepine exposure, thereby implicating specific TCRs in DH etiology.
- Ren-You Pan
- , Mu-Tzu Chu
- & Shuen-Iu Hung
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Article
| Open Access
Molecular constraints on CDR3 for thymic selection of MHC-restricted TCRs from a random pre-selection repertoire
For T cells, functional antigen receptors are selected in the thymus from a pre-selection repertoire by interaction with self MHCs. Here the authors show that specific, non-germline coded features located in the complementarity determining region 3 of the pre-selection antigen receptors are essential for the selection of MHC-restricted repertoire.
- Jinghua Lu
- , François Van Laethem
- & Peter D. Sun
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| Open Access
Runx-dependent and silencer-independent repression of a maturation enhancer in the Cd4 gene
The commitment of helper and cytotoxic lineages for CD4 and CD8 T cells, respectively, is associated with the regulation of Cd4 gene expression. Here the authors show that an intronic silencer, S4, has differential effects and synergy with the RUNX complex to act on two enhancer elements of the CD4 gene to control T cell lineage commitment in the thymus.
- Satoshi Kojo
- , Nighat Yasmin
- & Ichiro Taniuchi
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Article
| Open Access
Stage-specific epigenetic regulation of CD4 expression by coordinated enhancer elements during T cell development
The expression of CD4, a critical co-receptor providing T cell help in adaptive immunity, is finely tuned during development. Here the authors show that two enhancer elements, E4p and the newly-defined E4m, coordinate the expression and heritable demethylation of Cd4 in thymocytes but are dispensable for its sustained expression in peripheral T cells.
- Priya D. Issuree
- , Kenneth Day
- & Dan R. Littman
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Article
| Open Access
The human Vδ2+ T-cell compartment comprises distinct innate-like Vγ9+ and adaptive Vγ9- subsets
Human Vδ2+ γδ T cells are thought to be an innate-like T-cell population. Here the authors show the Vδ2+ compartment contains both innate-like Vγ9+ and an adaptive Vγ9- subset that undergoes clonal expansion during viral infection and can infiltrate liver tissue.
- Martin S. Davey
- , Carrie R. Willcox
- & Benjamin E. Willcox
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Article
| Open Access
Lymphotoxin α fine-tunes T cell clonal deletion by regulating thymic entry of antigen-presenting cells
Autoreactive T cells are removed during their development in the thymus through the functions of medullary thymic epithelial cells (mTEC) and dendritic cells (DC), a process termed negative selection. Here the authors show that mTEC-T cell crosstalk and lymphotoxin α signalling are essential for the proper recruitment of DCs into the thymus.
- Noëlla Lopes
- , Jonathan Charaix
- & Magali Irla
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| Open Access
Germinal center entry not selection of B cells is controlled by peptide-MHCII complex density
It has been thought that germinal center (GC) B cells with the highest density of peptide-MHCII molecules receive the most T cell help. Here the authors use heterozygous MHCII inactivation to instead show that after recruitment into the GCs, BCR affinity increases over time independent of the MHC density.
- Chen-Hao Yeh
- , Takuya Nojima
- & Garnett Kelsoe
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Article
| Open Access
Desensitized chimeric antigen receptor T cells selectively recognize target cells with enhanced antigen expression
Engineered T cells with chimeric antigen receptor (CAR) are emerging as an effective cancer therapy. Here the authors show that CAR T cells recognizing self-MHC can be ‘tuned’ ex vivo via CAR downregulation and CAR T cell death to generate a CAR T pool specifically targeting tumor cells with high MHC expression.
- Chungyong Han
- , Su-Jung Sim
- & Byoung S. Kwon
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| Open Access
NCoR1 restrains thymic negative selection by repressing Bim expression to spare thymocytes undergoing positive selection
Thymocytes are screened by two processes, termed positive and negative selections, which are permissive only for immature thymocytes with intermediate avidity to the selecting ligands. Here the authors show that the nuclear receptor NCoR1 suppresses Bim1 to inhibit negative selection and promote thymocyte survival.
- Jianrong Wang
- , Nanhai He
- & Qibin Leng
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Article
| Open Access
T follicular helper and T follicular regulatory cells have different TCR specificity
T follicular helper and regulatory cells are generated in the germinal centre; however, whether antigen specificity defines their differential functions is unclear. Here the authors show that T cells with distinct antigen specificity spectra are recruited to the germinal centre to establish these two populations.
- Ana Raquel Maceiras
- , Silvia Cristina Paiva Almeida
- & Luis Graca
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Article
| Open Access
Clonal selection in the human Vδ1 T cell repertoire indicates γδ TCR-dependent adaptive immune surveillance
γδ T cells are generally considered innate‐like lymphocytes. Here the authors sequence human γδ T cell receptors (TCR) to show focusing of the private Vδ1 TCR repertoire, suggesting that, unlike Vδ2 T cells, the Vδ1 T cell compartment has adaptive attributes.
- Martin S. Davey
- , Carrie R. Willcox
- & Benjamin E. Willcox
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Article
| Open Access
Foxn1-β5t transcriptional axis controls CD8+ T-cell production in the thymus
Foxn1 is involved in thymic epithelial cell (TEC) and CD8+T cell development. Here the authors show this development requires Foxn1 binding proximal to, and inducing transcription of, the gene encoding β5t in cortical TECs.
- Muhammad Myn Uddin
- , Izumi Ohigashi
- & Yousuke Takahama
Continually recruited naïve T cells contribute to the follicular helper and regulatory T cell pools in germinal centers