Biology subjects

Jurgens, A. P.

Publications and source records attributed to Jurgens, A. P..

3 recordsLinked to original sources

bioRxiv2026

An early mTOR-dependent window during human T cell activation programs T cell state

T cell activation results in profound proteome remodeling that programs T cells into distinct cellular states. The mechanistic target of rapamycin (mTOR) biases T cell differentiation toward a cytotoxic fate at the expense of memory-precursor formation, making mTOR inhibition an attractive strategy to boost T cell memory during vaccination. Here, we used matched time-resolved mRNA sequencing and quantitative mass spectrometry to define how the human T cell proteome is remodeled during the first 24 hours of activation. We found that human T cells rapidly remodel their proteome in distinct, temporally ordered modules that drive translation and proliferation while promoting a cytotoxic T cell state. Notably, mTOR inhibition during the first 24 hours of T cell activation perturbed these protein modules. Strikingly, transient mTOR inhibition limited to the first 16 hours of T cell priming was sufficient to imprint a memory-like T cell state, while preserving the capacity to produce inflammatory cytokines and mediate target cell killing. Together, these findings indicate that mTOR activity dictates stable functional trajectories during early T cell activation, revealing a therapeutic window to refine vaccination responses.

immunology↗

bioRxiv2024

mTOR signaling promotes cytokine production in T cells through 3UTR-mediated translation control

T cells are key contributors to clear our body from infected and malignant cells. When T cells respond to target cells, they undergo profound translational alterations. The evolutionary and highly conserved kinase mammalian target of rapamycin (mTOR) is a central mediator of T cell differentiation, homeostasis, and T cell activation, including the production of the key pro-inflammatory cytokines TNF, IL2, and IFN{gamma}. mTOR was shown to execute its translation activity through TOP motifs located in the 5 Untranslated region (5UTR) of its target genes. Here, we uncovered a distinct mechanism of mTOR signaling on cytokine production in T cells, which is under control of the 3UTR. Even though non-classical TOP motifs are present in cytokine 3UTRs, they do not contribute to mTOR-mediated translation regulation. Rather, AU-rich elements (AREs) are required for mTOR-mediated cytokine production. Furthermore, we discovered that the RNA binding protein DDX21 binds to 3UTR AREs and confers the mTOR-mediated translation control. In conclusion, we here present a previously unappreciated ARE-dependent, 3UTR-mediated mode of action that mTOR employs to regulate cytokine production.

immunology↗

bioRxiv2021

Time-dependent regulation of cytokine production by RNA binding proteins defines T cell effector function

Potent T cell responses against infections and malignancies depend on the release of effector molecules, such as pro-inflammatory cytokines. Because effector molecules can be toxic, their production is tightly regulated through post-transcriptional events at 3 Untranslated Regions (3UTRs). RNA binding proteins (RBPs) were shown to be key regulators herein. With an RNA aptamer-based capture assay from human T cells, we identified >130 RBPs interacting with the IFNG, TNF and IL2 3UTRs in human T cells. T cell activation altered RBP-RNA interactions, revealing that RBP-target mRNA interactions rapidly respond to stimulation. Furthermore, we uncovered the intricate and time-dependent regulation of cytokine production by RBPs: whereas HuR supports early cytokine production, ZFP36L1, ATXN2L and ZC3HAV1 dampen and shorten the production duration, each at different time points. Strikingly, even though ZFP36L1 deletion did not phenotypically rescue T cell dysfunction in tumors, the increased production of cytokines and cytotoxic molecules resulted in superior anti-tumoral T cell responses in vivo. Our findings thus show that identifying RBP-RNA interactions reveals key modulators of T cell responses in health and disease.

immunology↗