Optogenetic control shows that kinetic proofreading regulates the activity of the T cell receptor
- University of Freiburg, Germany
- German Cancer Research Center (DKFZ), Germany
- Wageningen UR, Netherlands
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.
Data availability
All data that were analyzed with the mathematical model are provided in source data files.
Article and author information
Author details
Wolfgang WA Schamel
Funding
Deutsche Forschungsgemeinschaft (GSC-4)
- O Sascha Yousefi
- Maximilian Hörner
Deutsche Forschungsgemeinschaft (EXC294)
- Wolfgang WA Schamel
Deutsche Forschungsgemeinschaft (EXC81)
- Thomas Höfer
Deutsche Forschungsgemeinschaft (EXC2189)
- Wolfgang WA Schamel
Deutsche Forschungsgemeinschaft (INST 39/899-1 FUGG)
- Wolfgang WA Schamel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Yousefi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 7,633
- views
-
- 1,158
- downloads
-
- 94
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Optogenetic control shows that kinetic proofreading regulates the activity of the T cell receptor
eLife 8:e42475.
https://doi.org/10.7554/eLife.42475
Further reading
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
HIV and simian immunodeficiency virus (SIV) infections are known for impaired neutralizing antibody (NAb) responses. While sequential virus–host B cell interaction appears to be basally required for NAb induction, driver molecular signatures predisposing to NAb induction still remain largely unknown. Here we describe SIV-specific NAb induction following a virus–host interplay decreasing aberrant viral drive of phosphoinositide 3-kinase (PI3K). Screening of seventy difficult-to-neutralize SIVmac239-infected macaques found nine NAb-inducing animals, with seven selecting for a specific CD8+ T-cell escape mutation in viral nef before NAb induction. This Nef-G63E mutation reduced excess Nef interaction-mediated drive of B-cell maturation-limiting PI3K/mammalian target of rapamycin complex 2 (mTORC2). In vivo imaging cytometry depicted preferential Nef perturbation of cognate Envelope-specific B cells, suggestive of polarized contact-dependent Nef transfer and corroborating cognate B-cell maturation post-mutant selection up to NAb induction. Results collectively exemplify a NAb induction pattern extrinsically reciprocal to human PI3K gain-of-function antibody-dysregulating disease and indicate that harnessing the PI3K/mTORC2 axis may facilitate NAb induction against difficult-to-neutralize viruses including HIV/SIV.
-
- Immunology and Inflammation
The T6SS of Pseudomonas aeruginosa plays an essential role in the establishment of chronic infections. Inflammasome-mediated inflammatory cytokines are crucial for host defense against bacterial infections. We found that P. aeruginosa infection activates the non-canonical inflammasome in macrophages, yet it inhibits the downstream activation of the NLRP3 inflammasome. The VgrG2b of P. aeruginosa is recognized and cleaved by caspase-11, generating a free C-terminal fragment. The VgrG2b C-terminus can bind to NLRP3, inhibiting the activation of the NLRP3 inflammasome by rejecting NEK7 binding to NLRP3. Administration of a specific peptide that inhibits caspase-11 cleavage of VgrG2b significantly improves mouse survival during infection. Our discovery elucidates a mechanism by which P. aeruginosa inhibits host immune response, providing a new approach for the future clinical treatment of P. aeruginosa infections.
