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

By 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

Posted 04 Sep 2019
bioRxiv DOI: 10.1101/753731 (published DOI: 10.1038/s41467-020-15543-y)

Naive 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 naive and memory CD4+ T cells to generate a detailed map of cytokine-regulated gene expression programs. We demonstrated that cytokine response differs substantially between naive 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 naive 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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