A Minimum Epitope Overlap between Infections Strongly Narrows the Emerging T Cell Repertoire

Oberle, Susanne; Hanna-El-Daher, Layane; Chennupati, Vijaykumar; Enouz, Sarah; Scherer, Stefanie; Prlic, Martin; Zehn, Dietmar

doi:10.1016/j.celrep.2016.09.072

Cited by 22 publications

(22 citation statements)

References 34 publications

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“…We wondered whether CD8.4 OT‐I T cells do respond to endogenous self‐antigens Catnb and Mapk8 that were previously proposed as positive selecting antigens for OT‐I T cells (Santori et al , ). In agreement with previous reports (Salmond et al , ; Oberle et al , ), we could not detect a substantial response of peripheral OT‐I T cells to these antigens in vitro using antigen‐loaded dendritic cells and in vivo using Lm‐Catnb (Fig EV5E and F). CD8.4 OT‐I T cells showed no significant response to these self‐peptides as well (Fig EV5E and F).…”

Section: Resultssupporting

confidence: 93%

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Strong homeostatic TCR signals induce formation of self‐tolerant virtual memory CD8 T cells

et al. 2018

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Virtual memory T cells are foreign antigen‐inexperienced T cells that have acquired memory‐like phenotype and constitute 10–20% of all peripheral CD8+ T cells in mice. Their origin, biological roles, and relationship to naïve and foreign antigen‐experienced memory T cells are incompletely understood. By analyzing T‐cell receptor repertoires and using retrogenic monoclonal T‐cell populations, we demonstrate that the virtual memory T‐cell formation is a so far unappreciated cell fate decision checkpoint. We describe two molecular mechanisms driving the formation of virtual memory T cells. First, virtual memory T cells originate exclusively from strongly self‐reactive T cells. Second, the stoichiometry of the CD8 interaction with Lck regulates the size of the virtual memory T‐cell compartment via modulating the self‐reactivity of individual T cells. Although virtual memory T cells descend from the highly self‐reactive clones and acquire a partial memory program, they are not more potent in inducing experimental autoimmune diabetes than naïve T cells. These data underline the importance of the variable level of self‐reactivity in polyclonal T cells for the generation of functional T‐cell diversity.

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Section: Resultssupporting

confidence: 93%

“…or with 5,000 CFU of Lm. Lm strains expressing OVA, Q4R7, and Q4H7 have been described previously (King et al, 2012;Oberle et al, 2016). Lm expressing NP68 was produced by adding the ASNENMDAM epitope to ovalbumin encoding gene and introduced to Lm as previously described (Zehn et al, 2009).…”

Section: In Vivo Activation and A Model For Autoimmune Diabetesmentioning

confidence: 99%

Strong homeostatic TCR signals induce formation of self‐tolerant virtual memory CD8 T cells

et al. 2018

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“…These direct measurements of TCR mechanical sampling and scanning agree well with previous single-molecule force spectroscopy measurements, where forces were applied externally to determine 2D kinetics and affinity (23). We also found that the mechanical sampling and scanning factors were both highly correlated to the potency of these antigens (as measured using published cytokine production assays) (24,25), further underscoring the potential of these mechanical parameters as readouts of T cell activation (Fig. 3F).…”

Section: Resultssupporting

confidence: 86%

DNA probes that store mechanical information reveal transient piconewton forces applied by T cells

Kellner

Pui‐Yan

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

107

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The advent of molecular tension probes for real-time mapping of piconewton forces in living systems has had a major impact on mechanobiology. For example, DNA-based tension probes have revealed roles for mechanics in platelet, B cell, T cell, and fibroblast function. Nonetheless, imaging short-lived forces transmitted by low-abundance receptors remains a challenge. This is a particular problem for mechanoimmunology where ligand–receptor bindings are short lived, and a few antigens are sufficient for cell triggering. Herein, we present a mechanoselection strategy that uses locking oligonucleotides to preferentially and irreversibly bind DNA probes that are mechanically strained over probes at rest. Thus, infrequent and short-lived mechanical events are tagged. This strategy allows for integration and storage of mechanical information into a map of molecular tension history. Upon addition of unlocking oligonucleotides that drive toehold-mediated strand displacement, the probes reset to the real-time state, thereby erasing stored mechanical information. As a proof of concept, we applied this strategy to study OT-1 T cells, revealing that the T cell receptor (TCR) mechanically samples antigens carrying single amino acid mutations. Such events are not detectable using conventional tension probes. Each mutant peptide ligand displayed a different level of mechanical sampling and spatial scanning by the TCR that strongly correlated with its functional potency. Finally, we show evidence that T cells transmit pN forces through the programmed cell death receptor-1 (PD1), a major target in cancer immunotherapy. We anticipate that mechanical information storage will be broadly useful in studying the mechanobiology of the immune system.

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“…For example, preexisting T memory (Tm) cells can restrict the priming of protective naïve T cells to heterologous antigen [25]. Furthermore, pre-existing Tm cells can narrow the primary T cell response by shifting towards proliferation of high affinity clones only [26]. A narrowed T cell response may lead to escape variants and has been shown to be associated with severe disease progression [27,28].…”

Section: Heterologous Immunitymentioning

confidence: 99%

Respiratory virus-induced heterologous immunity

2018

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Purpose To provide current knowledge on respiratory virus-induced heterologous immunity (HI) with a focus on humoral and cellular cross-reactivity. Adaptive heterologous immune responses have broad implications on infection, autoimmunity, allergy and transplant immunology. A better understanding of the mechanisms involved might ultimately open up possibilities for disease prevention, for example by vaccination. Methods A structured literature search was performed using Medline and PubMed to provide an overview of the current knowledge on respiratory-virus induced adaptive HI.

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A Minimum Epitope Overlap between Infections Strongly Narrows the Emerging T Cell Repertoire

Cited by 22 publications

References 34 publications

Strong homeostatic TCR signals induce formation of self‐tolerant virtual memory CD8 T cells

Strong homeostatic TCR signals induce formation of self‐tolerant virtual memory CD8 T cells

DNA probes that store mechanical information reveal transient piconewton forces applied by T cells

Respiratory virus-induced heterologous immunity

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