Biology subjects

van der Zwaan, C.

Publications and source records attributed to van der Zwaan, C..

3 recordsLinked to original sources

bioRxiv2026

Proteomics of human cancer-associated T cells identifies regulators of T cell functionality

CD8+ T cells in solid cancers progressively lose anti-tumor activity, yet the cell-intrinsic mechanisms driving this loss of function remain incompletely defined. Here, we performed matched proteomic and transcriptomic profiling of dysfunctional and bystander CD8+ tumor-infiltrating T cells isolated from primary tumors of treatment-naive non-small cell lung cancer patients. Proteomic analysis revealed widespread discordance with mRNA expression, with 8% of all quantified proteins displaying differential expression exclusively at the protein level. Genetic perturbation of such differentially expressed proteins identified the chromatin remodeler CHD4 and fatty acid synthase (FASN) as cell-intrinsic regulators of T cell function. CHD4 deletion resulted in altered gene-regulatory networks that promoted effector differentiation and enhanced cytokine production. In contrast, FASN deletion preserved mitochondrial fitness and sustained T cell functionality under chronic T cell receptor stimulation. Together, these findings demonstrate that proteomic profiling uncovers regulators of T cell functionality that are not apparent from transcriptomic analyses alone, highlighting an additional layer of regulatory control.

immunology↗

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

Combined deletion of ZFP36L1 and ZFP36L2 drives superior cytokine production in T cells at the cost of cell fitness

A key feature of cytotoxic CD8+ T cells for eliminating pathogens and malignant cells is their capacity to produce pro-inflammatory cytokines, which includes TNF and IFN{gamma}. Provided that these cytokines are highly toxic, a tight control of their production is imperative. RNA-binding proteins (RBPs) are essential for the fine-tuning of cytokine production. The role of the RBP ZFP36L1 and its sister protein ZFP36L2 herein has been established, however, their relative contribution to cytokine production is not well known. We here compared the effect of ZFP36L1 and ZFP36L2 single and double deficiency in murine effector CD8+ T cells. Whereas single deficient T cells significantly increased cytokine production, double deficiency completely unleashed the cytokine production. Not only the TNF production was substantially prolonged in double-deficient T cells. Also, the production of IFN{gamma} reached unprecedented levels with >90% IFN{gamma}-producing T cells compared to 3% in WT T cells, even after 3 days of continuous activation. This continuous cytokine production by double-deficient T cells was also observed in tumor-infiltrating lymphocytes in vivo, however, with no effect on tumor growth. Rather, ZFP36L1 and ZFP36L2 double deficiency resulted in decreased cell viability, impaired STAT5 signaling, and dysregulated cell cycle progression. In conclusion, while combined deletion in ZFP36L1 and ZFP36L2 can drive continuous cytokine production even under chronic activation, safeguards are in place to counteract such super-cytokine producers.

immunology↗