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

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. Here we use quantitative proteomics, bulk RNA-seq, and single-cell RNA-seq of over 40,000 human naive 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 naive 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. Cytokines critically control the differentiation and functions of activated naive and memory T cells. Here the authors show, using multi-omics and single-cell analyses, that naive and memory T cells exhibit distinct cytokine responses, in which an 'effectorness gradient' is depicted by a transcriptional continuum, which shapes the downstream genetic programs.