T Cells Decode Pulsed TCR Signals via Pause-Sensitive Transcription Factors

Le September 29 2025 at 11h00 Séminaire

T Cells Decode Pulsed TCR Signals via Pause-Sensitive Transcription Factors

Vincent Idstein¹, Anna K. Ehret¹, Emmanuelle Moraes¹, Sara Hartmann¹, Jonas Gretz¹, Nila H. Servaas², Sascha Yousefi¹, Susana Minguet¹, Judith Zaugg², Sagar¹, Wolfgang W. Schamel¹

¹University of Freiburg, ²EMBL Heidelberg, Germany

While migrating, immune cells are exposed to dynamic and complex patterns of stimulation in vivo. For example, at a high antigen density, a T cell will encounter the same stimulus from antigen-presenting cells (APCs) very frequently, while at low density, encounters are rare and separated by long pauses. It remains unclear whether T cells can interpret the information encoded in these temporal stimulation patterns. Hence, the molecular mechanisms and functional implications of such decoding are unknown - largely due to the lack of technologies that can precisely manipulate temporal patterns. To address this challenge, we used an optogenetic system that allows precise control of TCR-ligand binding in primary T cells. By applying defined light-dependent temporal stimulation patterns and analyzing transcriptomic changes at the single-cell level, we uncover a previously unrecognized sensitivity of T cells to the timing of TCR engagements. Our findings reveal that naïve T cells are exquisitely tuned to the temporal structure of stimulation. As expected, most transcription factors, including NFAT, show reduced activity as the duration of inter-stimulation pauses increases. Strikingly, however, a regulatory network of eleven transcription factors - including members of the NFkB, NR4A, and EGR families - shows enhanced activity with longer pauses. Our results indicate that T cells do more than sum the total time of stimulation and reveal distinct temporal memory within their transcriptional machinery that mechanistically explains their varied responses to different pause durations. As a consequence, with short pauses the cells proliferate strongly. This reflects a situation of high antigen load, where the few specific T cells must rapidly expand in number to control the infection. With long pauses (low antigen load) the T cells tend to differentiate, such as to Th17 T cells. Our data show that these fate decisions are made very early during naïve T cell priming.