IL-17 cytokines preferentially act on naive CD4+ T cells with IL-17AF inducing the greatest transcriptomic changes.

Abstract

Abstract CD4+ T-helper 17 (Th17) T cells are important in the regulation of protective immunity during infection and in self-tolerance/autoimmunity. Th17 cells, through the secretion of IL-17, act in promotion of inflammation and are thus a major potential therapeutic target in autoimmune disorders. Recent reports show that the IL-17 family cytokines, IL-17A, IL-17F and IL-17AF, can directly act on CD4+ T-cells, inducing functional changes in these cells. Here we show that functional and transcriptomic changes were preferentially induced in naïve CD4+ T-cells, but not in memory CD4+ T-cells. As early as 48 hours post-IL-17 exposure, naïve cells showed transcriptome changes, whereas memory cells remained unaffected as late as 7 days. The functional differences occurred despite similar IL-17RC and IL-17RA receptor expression on these subsets. Also, the differential IL-17-mediated changes in naïve, but not memory, cells occurred even in transwell/co-culture systems, with each subset maintaining its respective functional phenotype. Notably, there were differences in downstream transcriptional signaling by the three IL-17 cytokines. The IL-17AF heterodimer conferred both the greatest transcriptional change and most altered functional consequences. Detailed analysis of the transcriptome provides important insights into the genes and pathways that are altered as a result of IL-17-induced signaling and may serve as targets of future therapies. This work was supported, in part, by grant awards from the NIH to N.J.K. (R01 AI121567) and N.B. (F30 CA29655).