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Article ; Online: Harnessing CD3 diversity to optimize CAR T cells.

Velasco Cárdenas, Rubí M-H / Brandl, Simon M / Meléndez, Ana Valeria / Schlaak, Alexandra Emilia / Buschky, Annabelle / Peters, Timo / Beier, Fabian / Serrels, Bryan / Taromi, Sanaz / Raute, Katrin / Hauri, Simon / Gstaiger, Matthias / Lassmann, Silke / Huppa, Johannes B / Boerries, Melanie / Andrieux, Geoffroy / Bengsch, Bertram / Schamel, Wolfgang W / Minguet, Susana

Nature immunology

2023 Volume 24, Issue 12, Page(s) 2135–2149

Abstract: Current US Food and Drug Administration-approved chimeric antigen receptor (CAR) T cells harbor the T cell receptor (TCR)-derived ζ chain as an intracellular activation domain in addition to costimulatory domains. The functionality in a CAR format of the ...

Abstract	Current US Food and Drug Administration-approved chimeric antigen receptor (CAR) T cells harbor the T cell receptor (TCR)-derived ζ chain as an intracellular activation domain in addition to costimulatory domains. The functionality in a CAR format of the other chains of the TCR complex, namely CD3δ, CD3ε and CD3γ, instead of ζ, remains unknown. In the present study, we have systematically engineered new CD3 CARs, each containing only one of the CD3 intracellular domains. We found that CARs containing CD3δ, CD3ε or CD3γ cytoplasmic tails outperformed the conventional ζ CAR T cells in vivo. Transcriptomic and proteomic analysis revealed differences in activation potential, metabolism and stimulation-induced T cell dysfunctionality that mechanistically explain the enhanced anti-tumor performance. Furthermore, dimerization of the CARs improved their overall functionality. Using these CARs as minimalistic and synthetic surrogate TCRs, we have identified the phosphatase SHP-1 as a new interaction partner of CD3δ that binds the CD3δ-ITAM on phosphorylation of its C-terminal tyrosine. SHP-1 attenuates and restrains activation signals and might thus prevent exhaustion and dysfunction. These new insights into T cell activation could promote the rational redesign of synthetic antigen receptors to improve cancer immunotherapy.
MeSH term(s)	Proteomics ; CD3 Complex ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Cell Membrane/metabolism ; Lymphocyte Activation ; T-Lymphocytes
Chemical Substances	CD3 Complex ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-11-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-023-01658-z
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Article ; Online: NLRC5 promotes transcription of

Dang, Anh Thu / Strietz, Juliane / Zenobi, Alessandro / Khameneh, Hanif J / Brandl, Simon M / Lozza, Laura / Conradt, Gregor / Kaufmann, Stefan H E / Reith, Walter / Kwee, Ivo / Minguet, Susana / Chelbi, Sonia T / Guarda, Greta

iScience

2020 Volume 24, Issue 1, Page(s) 101900

Abstract: BTN3A molecules-BTN3A1 in particular-emerged as important mediators of Vγ9Vδ2 T cell activation by phosphoantigens. These metabolites can originate from infections, e.g. ... ...

Abstract	BTN3A molecules-BTN3A1 in particular-emerged as important mediators of Vγ9Vδ2 T cell activation by phosphoantigens. These metabolites can originate from infections, e.g. with
Language	English
Publishing date	2020-12-07
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2020.101900
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Article ; Online: Optogenetic control of gene expression in plants in the presence of ambient white light.

Ochoa-Fernandez, Rocio / Abel, Nikolaj B / Wieland, Franz-Georg / Schlegel, Jenia / Koch, Leonie-Alexa / Miller, J Benjamin / Engesser, Raphael / Giuriani, Giovanni / Brandl, Simon M / Timmer, Jens / Weber, Wilfried / Ott, Thomas / Simon, Rüdiger / Zurbriggen, Matias D

Nature methods

2020 Volume 17, Issue 7, Page(s) 717–725

Abstract: Optogenetics is the genetic approach for controlling cellular processes with light. It provides spatiotemporal, quantitative and reversible control over biological signaling and metabolic processes, overcoming limitations of chemically inducible systems. ...

Abstract	Optogenetics is the genetic approach for controlling cellular processes with light. It provides spatiotemporal, quantitative and reversible control over biological signaling and metabolic processes, overcoming limitations of chemically inducible systems. However, optogenetics lags in plant research because ambient light required for growth leads to undesired system activation. We solved this issue by developing plant usable light-switch elements (PULSE), an optogenetic tool for reversibly controlling gene expression in plants under ambient light. PULSE combines a blue-light-regulated repressor with a red-light-inducible switch. Gene expression is only activated under red light and remains inactive under white light or in darkness. Supported by a quantitative mathematical model, we characterized PULSE in protoplasts and achieved high induction rates, and we combined it with CRISPR-Cas9-based technologies to target synthetic signaling and developmental pathways. We applied PULSE to control immune responses in plant leaves and generated Arabidopsis transgenic plants. PULSE opens broad experimental avenues in plant research and biotechnology.
MeSH term(s)	Arabidopsis/genetics ; Arabidopsis/immunology ; CRISPR-Cas Systems/genetics ; Gene Expression Regulation, Plant ; Light ; Models, Theoretical ; Optogenetics ; Plants, Genetically Modified
Language	English
Publishing date	2020-06-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2169522-2
ISSN	1548-7105 ; 1548-7091
ISSN (online)	1548-7105
ISSN	1548-7091
DOI	10.1038/s41592-020-0868-y
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Article ; Online: Optogenetic control shows that kinetic proofreading regulates the activity of the T cell receptor.

Yousefi, O Sascha / Günther, Matthias / Hörner, Maximilian / Chalupsky, Julia / Wess, Maximilian / Brandl, Simon M / Smith, Robert W / Fleck, Christian / Kunkel, Tim / Zurbriggen, Matias D / Höfer, Thomas / Weber, Wilfried / Schamel, Wolfgang Wa

eLife

2019 Volume 8

Abstract: The immune system distinguishes between self and foreign antigens. The kinetic proofreading (KPR) model proposes that T cells discriminate self from foreign ligands by the different ligand binding half-lives to the T cell receptor (TCR). It is ... ...

Abstract	The immune system distinguishes between self and foreign antigens. The kinetic proofreading (KPR) model proposes that T cells discriminate self from foreign ligands by the different ligand binding half-lives to the T cell receptor (TCR). It is challenging to test KPR as the available experimental systems fall short of only altering the binding half-lives and keeping other parameters of the interaction unchanged. We engineered an optogenetic system using the plant photoreceptor phytochrome B (PhyB) as a ligand to selectively control the dynamics of ligand binding to the TCR by light. This opto-ligand-TCR system was combined with the unique property of PhyB to continuously cycle between the binding and non-binding states under red light, with the light intensity determining the cycling rate and thus the binding duration. Mathematical modeling of our experimental datasets showed that indeed the ligand-TCR interaction half-life is the decisive factor for activating downstream TCR signaling, substantiating KPR.
MeSH term(s)	Antigens/metabolism ; Humans ; Jurkat Cells ; Kinetics ; Light ; Models, Theoretical ; Optogenetics/methods ; Phytochrome B/metabolism ; Protein Binding ; Receptors, Antigen, T-Cell/metabolism ; Signal Transduction ; T-Lymphocytes/immunology
Chemical Substances	Antigens ; Receptors, Antigen, T-Cell ; Phytochrome B (136250-22-1)
Language	English
Publishing date	2019-04-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.42475
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Article ; Online: Erratum to: Optogenetics in Plants: Red/Far-Red Light Control of Gene Expression.

Ochoa-Fernandez, Rocio / Samodelov, Sophia L / Brandl, Simon M / Wehinger, Elke / Müller, Konrad / Weber, Wilfried / Zurbriggen, Matias D

Methods in molecular biology (Clifton, N.J.)

2016 Volume 1408, Page(s) E1

Language	English
Publishing date	2016
Publishing country	United States
Document type	Published Erratum
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-3512-3_28
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Article ; Online: Optogenetics in Plants: Red/Far-Red Light Control of Gene Expression.

Ochoa-Fernandez, Rocio / Samodelov, Sophia L / Brandl, Simon M / Wehinger, Elke / Müller, Konrad / Weber, Wilfried / Zurbriggen, Matias D

Methods in molecular biology (Clifton, N.J.)

2016 Volume 1408, Page(s) 125–139

Abstract: Optogenetic tools to control gene expression have many advantages over the classical chemically inducible systems, overcoming intrinsic limitations of chemical inducers such as solubility, diffusion, and cell toxicity. They offer an unmatched ... ...

Abstract	Optogenetic tools to control gene expression have many advantages over the classical chemically inducible systems, overcoming intrinsic limitations of chemical inducers such as solubility, diffusion, and cell toxicity. They offer an unmatched spatiotemporal resolution and permit quantitative and noninvasive control of the gene expression. Here we describe a protocol of a synthetic light-inducible system for the targeted control of gene expression in plants based on the plant photoreceptor phytochrome B and one of its interacting factors (PIF6). The synthetic toggle switch system is in the ON state when plant protoplasts are illuminated with red light (660 nm) and can be returned to the OFF state by subsequent illumination with far-red light (760 nm). In this protocol, the implementation of a red light-inducible expression system in plants using Light-Emitting Diode (LED) illumination boxes is described, including the isolation and transient transformation of plant protoplasts from Arabidopsis thaliana and Nicotiana tabacum.
MeSH term(s)	Arabidopsis/genetics ; Arabidopsis/metabolism ; Arabidopsis/radiation effects ; Arabidopsis Proteins/genetics ; Arabidopsis Proteins/metabolism ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Gene Expression Regulation, Plant/radiation effects ; Light ; Luminescent Measurements/methods ; Optogenetics/methods ; Phytochrome B/genetics ; Phytochrome B/metabolism ; Plant Proteins/genetics ; Plant Proteins/metabolism ; Protoplasts/metabolism ; Protoplasts/radiation effects ; Nicotiana/genetics ; Nicotiana/metabolism ; Nicotiana/radiation effects
Chemical Substances	Arabidopsis Proteins ; Basic Helix-Loop-Helix Transcription Factors ; PIF6 protein, Arabidopsis ; Plant Proteins ; Phytochrome B (136250-22-1)
Language	English
Publishing date	2016-02-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-3512-3_9
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Species richness and identity both determine the biomass of global reef fish communities

Lefcheck, Jonathan S. / Edgar, Graham J. / Stuart-Smith, Rick D. / Bates, Amanda E. / Waldock, Conor / id_orcid:0 000-0002-2818-9859 / Brandl, Simon M. / Kininmonth, Stuart / Ling, Scott D. / Duffy, J. Emmett / Rasher, Douglas B. / Agrawal, Aneil F.

Nature Communications, 12 (1)

2021

Abstract: Changing biodiversity alters ecosystem functioning in nature, but the degree to which this relationship depends on the taxonomic identities rather than the number of species remains untested at broad scales. Here, we partition the effects of declining ... ...

Abstract	Changing biodiversity alters ecosystem functioning in nature, but the degree to which this relationship depends on the taxonomic identities rather than the number of species remains untested at broad scales. Here, we partition the effects of declining species richness and changing community composition on fish community biomass across >3000 coral and rocky reef sites globally. We find that high biodiversity is 5.7x more important in maximizing biomass than the remaining influence of other ecological and environmental factors. Differences in fish community biomass across space are equally driven by both reductions in the total number of species and the disproportionate loss of larger-than-average species, which is exacerbated at sites impacted by humans. Our results confirm that sustaining biomass and associated ecosystem functions requires protecting diversity, most importantly of multiple large-bodied species in areas subject to strong human influences. ISSN:2041-1723
Keywords	Biodiversity ; Community ecology ; Ocean sciences
Subject code	333
Language	English
Publisher	Nature
Publishing country	ch
Document type	Article ; Online
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Article ; Online: Author Correction: Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function.

Nature immunology

2020 Volume 22, Issue 1, Page(s) 100–101

Language	English
Publishing date	2020-11-17
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-020-00843-8
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Zs.A 5294: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function.

Nature immunology

2020 Volume 21, Issue 8, Page(s) 902–913

Abstract: Initiation of T cell antigen receptor (TCR) signaling involves phosphorylation of CD3 cytoplasmic tails by the tyrosine kinase Lck. How Lck is recruited to the TCR to initiate signaling is not well known. We report a previously unknown binding motif in ... ...

Abstract	Initiation of T cell antigen receptor (TCR) signaling involves phosphorylation of CD3 cytoplasmic tails by the tyrosine kinase Lck. How Lck is recruited to the TCR to initiate signaling is not well known. We report a previously unknown binding motif in the CD3ε cytoplasmic tail that interacts in a noncanonical mode with the Lck SH3 domain: the receptor kinase (RK) motif. The RK motif is accessible only upon TCR ligation, demonstrating how ligand binding leads to Lck recruitment. Binding of the Lck SH3 domain to the exposed RK motif resulted in local augmentation of Lck activity, CD3 phosphorylation, T cell activation and thymocyte development. Introducing the RK motif into a well-characterized 41BB-based chimeric antigen receptor enhanced its antitumor function in vitro and in vivo. Our findings underscore how a better understanding of the functioning of the TCR might promote rational improvement of chimeric antigen receptor design for the treatment of cancer.
MeSH term(s)	Amino Acid Motifs/immunology ; Animals ; CD3 Complex/immunology ; CD3 Complex/metabolism ; Humans ; Lymphocyte Activation/immunology ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/immunology ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism ; Mice ; Receptors, Antigen, T-Cell/immunology ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Chimeric Antigen/immunology
Chemical Substances	CD3 Complex ; Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) (EC 2.7.10.2)
Language	English
Publishing date	2020-07-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-020-0732-3
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Zs.A 5294: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Optogenetic control shows that kinetic proofreading regulates the activity of the T cell receptor

Yousefi, O.S. / Günther, Matthias / Hörner, Maximilian / Chalupsky, Julia / Wess, Maximilian / Brandl, Simon M. / Smith, Robert W. / Fleck, Christian / Kunkel, Tim / Zurbriggen, Matias D. / Höfer, Thomas / Weber, Wilfried / Schamel, Wolfgang W.A.

eLife

2019 Volume 8

Abstract	The immune system distinguishes between self and foreign antigens. The kinetic proofreading (KPR) model proposes that T cells discriminate self from foreign ligands by the different ligand binding half-lives to the T cell receptor (TCR). It is challenging to test KPR as the available experimental systems fall short of only altering the binding half-lives and keeping other parameters of the interaction unchanged. We engineered an optogenetic system using the plant photoreceptor phytochrome B (PhyB) as a ligand to selectively control the dynamics of ligand binding to the TCR by light. This opto-ligand-TCR system was combined with the unique property of PhyB to continuously cycle between the binding and non-binding states under red light, with the light intensity determining the cycling rate and thus the binding duration. Mathematical modeling of our experimental datasets showed that indeed the ligand-TCR interaction half-life is the decisive factor for activating downstream TCR signaling, substantiating KPR.
Keywords	A. thaliana ; T cells ; dynamics ; human ; immunology ; inflammation ; ligand-receptor ; optogenetics ; signaling
Subject code	570
Language	English
Publishing country	nl
Document type	Article ; Online
ZDB-ID	2687154-3
ISSN	2050-084X
ISSN	2050-084X
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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