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
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. Here we use quantitative proteomics, bulk RNA-seq, and single-cell RNA-seq of over 40,000 human naïve and memory CD4+ T cells to show that responses to cytokines differ substantially between these cell types. Memory T cells are unable to differentiate into the Th2 phenotype, and acquire a Th17-like phenotype in response to iTreg polarization. Single-cell analyses show that T cells constitute a transcriptional continuum that progresses from naïve to central and effector memory T cells, forming an effectorness gradient accompanied by an increase in the expression of chemokines and cytokines. Finally, we show that T cell activation and cytokine responses are influenced by the effectorness gradient. Our results illustrate the heterogeneity of T cell responses, furthering our understanding of inflammation.