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Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4+ T cells to cytokines

View ORCID ProfileEddie Cano-Gamez, View ORCID ProfileBlagoje Soskic, View ORCID ProfileTheodoros I. Roumeliotis, Ernest So, View ORCID ProfileDeborah J. Smyth, View ORCID ProfileMarta Baldrighi, David Willé, Nikolina Nakic, Jorge Esparza-Gordillo, Christopher G. C. Larminie, Paola G. Bronson, David F. Tough, Wendy C. Rowan, View ORCID ProfileJyoti S. Choudhary, View ORCID ProfileGosia Trynka
doi: https://doi.org/10.1101/753731
Eddie Cano-Gamez
1Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK
2Open Targets, Wellcome Genome Campus, Cambridge CB10 1SA, UK
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Blagoje Soskic
1Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK
2Open Targets, Wellcome Genome Campus, Cambridge CB10 1SA, UK
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  • For correspondence: gosia@sanger.ac.uk bs11@sanger.ac.uk
Theodoros I. Roumeliotis
3Functional Proteomics, The Institute for Cancer Research, London, SW3 6JB, UK
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  • ORCID record for Theodoros I. Roumeliotis
Ernest So
3Functional Proteomics, The Institute for Cancer Research, London, SW3 6JB, UK
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Deborah J. Smyth
1Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK
2Open Targets, Wellcome Genome Campus, Cambridge CB10 1SA, UK
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Marta Baldrighi
1Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK
2Open Targets, Wellcome Genome Campus, Cambridge CB10 1SA, UK
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David Willé
4Biostatistics, GSK Medicines Research Centre, Stevenage, UK, SG1 2NY, UK
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Nikolina Nakic
5Functional Genomics, Molecular Science and Technology R&D, GSK Medicines Research Centre, Stevenage, SG1 2NY, UK
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Jorge Esparza-Gordillo
6Human Genetics, GSK Medicines Research Centre, Stevenage, UK, SG1 2NY, UK
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Christopher G. C. Larminie
6Human Genetics, GSK Medicines Research Centre, Stevenage, UK, SG1 2NY, UK
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Paola G. Bronson
7Human Target Validation Core, RED Translational Biology, Biogen, Cambridge, MA, USA
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David F. Tough
8Epigenetics RU,Oncology R&D, GSK, Medicines Research Centre, Stevenage SG1 2NY, UK
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Wendy C. Rowan
9Novel Human Genetics, GSK R&D, Stevenage SG1 2NY, UK
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Jyoti S. Choudhary
3Functional Proteomics, The Institute for Cancer Research, London, SW3 6JB, UK
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Gosia Trynka
1Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK
2Open Targets, Wellcome Genome Campus, Cambridge CB10 1SA, UK
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  • ORCID record for Gosia Trynka
  • For correspondence: gosia@sanger.ac.uk bs11@sanger.ac.uk
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Abstract

Naïve CD4+ T cells coordinate the immune response by acquiring an effector phenotype in response to cytokines. However, the cytokine responses in memory T cells remain largely understudied. We used quantitative proteomics, bulk RNA-seq and single-cell RNA-seq of over 40,000 human naïve and memory CD4+ T cells to generate a detailed map of cytokine-regulated gene expression programs. We demonstrated that cytokine response differs substantially between naïve and memory T cells and showed that memory cells are unable to differentiate into the Th2 phenotype. Moreover, memory T cells acquire a Th17-like phenotype in response to iTreg polarization. At the single-cell level, we demonstrated that T cells form a continuum which progresses from naïve to effector memory T cells. This continuum is accompanied by a gradual increase in the expression levels of chemokines and cytokines and thus represents an effectorness gradient. Finally, we found that T cell cytokine responses are determined by where the cells lie in the effectorness gradient and identified genes whose expression is controlled by cytokines in an effectorness-dependent manner. Our results shed light on the heterogeneity of T cells and their responses to cytokines, provide insight into immune disease inflammation and could inform drug development.

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Posted September 04, 2019.
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Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4+ T cells to cytokines
Eddie Cano-Gamez, Blagoje Soskic, Theodoros I. Roumeliotis, Ernest So, Deborah J. Smyth, Marta Baldrighi, David Willé, Nikolina Nakic, Jorge Esparza-Gordillo, Christopher G. C. Larminie, Paola G. Bronson, David F. Tough, Wendy C. Rowan, Jyoti S. Choudhary, Gosia Trynka
bioRxiv 753731; doi: https://doi.org/10.1101/753731
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Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4+ T cells to cytokines
Eddie Cano-Gamez, Blagoje Soskic, Theodoros I. Roumeliotis, Ernest So, Deborah J. Smyth, Marta Baldrighi, David Willé, Nikolina Nakic, Jorge Esparza-Gordillo, Christopher G. C. Larminie, Paola G. Bronson, David F. Tough, Wendy C. Rowan, Jyoti S. Choudhary, Gosia Trynka
bioRxiv 753731; doi: https://doi.org/10.1101/753731

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