Differential Interleukin-2 Transcription Kinetics Render Mouse but Not Human T Cells Vulnerable to Splicing Inhibition Early after Activation

ABSTRACT

T cells are nodal players in the adaptive immune response against pathogens and malignant cells. Alternative splicing plays a crucial role in T cell activation, which is analyzed mainly at later time points upon stimulation. Here we have discovered a 2-h time window early after stimulation where optimal splicing efficiency or, more generally, gene expression efficiency is crucial for successful T cell activation. Reducing the splicing efficiency at 4 to 6 h poststimulation significantly impaired murine T cell activation, which was dependent on the expression dynamics of the Egr1–Nab2–interleukin-2 (IL-2) pathway. This time window overlaps the time of peak IL-2 de novo transcription, which, we suggest, represents a permissive time window in which decreased splicing (or transcription) efficiency reduces mature IL-2 production, thereby hampering murine T cell activation. Notably, the distinct expression kinetics of the Egr1–Nab2–IL-2 pathway between mouse and human render human T cells refractory to this vulnerability. We propose that the rational temporal modulation of splicing or transcription during peak de novo expression of key effectors can be used to fine-tune stimulation-dependent biological outcomes. Our data also show that critical consideration is required when extrapolating mouse data to the human system in basic and translational research.

KEYWORDS:

• interleukin-2
• RNA splicing
• T cell activation
• gene expression

ACKNOWLEDGMENTS

We thank the HPC Service of ZEDAT, Freie Universität Berlin, for computing time. We also thank members of the F. Heyd laboratory for discussion and comments on the manuscript.

Funding was provided by DFG grant 278001972-TRR 186 to F.H.

D.B. performed all wet lab experiments. S.M. contributed to work with primary human T cells. A.N. performed bioinformatics analysis. B.T. performed RNA-Seq. Experimental design, data analysis, and writing of the manuscript were done by D.B. and F.H. F.H. conceived the project and supervised the work.