Integrative Multi-Omics Identifies CDK1 as a Key Signaling Regulator of CD4+ T Cell Effector Function

Servaas, N. H.; Bauersachs, H. G.; Abreu, L.; Claringbould, A.; Berest, I.; Schwarz, J. J.; Stein, F.; Faelth-Savitski, M.; Eismann, L.; Reddington, J. P.; Zaugg, J. B.

doi:10.1101/2025.10.30.685551

bioRxiv · 10.1101/2025.10.30.685551

Integrative Multi-Omics Identifies CDK1 as a Key Signaling Regulator of CD4+ T Cell Effector Function

Servaas, N. H.·Bauersachs, H. G.·Abreu, L.·Claringbould, A.·Berest, I.·Schwarz, J. J.·Stein, F.·Faelth-Savitski, M.·Eismann, L.·Reddington, J. P.·Zaugg, J. B.

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Abstract

CD4 T cell differentiation is orchestrated by coordinated signaling, transcriptional, and epigenomic programs, yet how signaling connects to chromatin and genetic variation in human T cells remains unclear. Here, we generated an integrative multi-omics map of human CD4 T cell activation and differentiation, combining phosphoproteomics, transcriptomics, and chromatin accessibility under Th0, Th1, and iTreg polarization. Within 10 minutes of activation, we observed rapid phosphorylation changes of RNA-binding proteins accompanied by degradation of effector-associated transcripts, preceding chromatin remodeling and later transcriptional activation of the same genes. Moreover, our data highlights how site-specific phosphorylation refines TF activity during T cell differentiation and activation, and identifies CDK1 as a regulator of Th1 effector function. Indeed, we found that a low dose of CKD1 inhibition impairs IFN-{gamma} expression and pro-inflammatory differentiation, while preserving regulatory features in iTregs. Single-cell multi-omic profiling upon CDK1 inhibition revealed how CDK1 activity shapes subset-specific gene regulatory networks, which are enriched for genetic variants associated with immune-traits. Specifically, CDK1-sensitive TFs, including IRF8, connect immune trait heritability to enhancer accessibility at IFNG and TNF loci. Together, these results establish CDK1 as a signaling hub that couples phosphorylation to gene regulation and genetic risk, with therapeutic relevance in autoimmune disease.

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Servaas, N. H., Bauersachs, H. G., Abreu, L., Claringbould, A., Berest, I., Schwarz, J. J., Stein, F., Faelth-Savitski, M., Eismann, L., Reddington, J. P., Zaugg, J. B.. 2025-10-31. Integrative Multi-Omics Identifies CDK1 as a Key Signaling Regulator of CD4+ T Cell Effector Function. https://doi.org/10.1101/2025.10.30.685551

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