Biology subjects

de Jesus, M.

Publications and source records attributed to de Jesus, M..

3 recordsLinked to original sources

bioRxiv2025

MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion

Loss of mitochondrial function contributes to CD8+ T cell dysfunction during persistent antigen encounter. How chronic antigen leads to this metabolic dysfunction remains unclear. Here, we show that TCR-dependent mitochondrial NADH accumulation drives production of ROS, ultimately leading to mitochondrial dysfunction. Among TCR-dependent proximal signaling components, MEK inhibition uniquely reduced nutrient uptake and mitochondrial NADH accumulation while increasing proliferation. As a result, MEK inhibition during chronic TCR stimulation reduced terminal T cell exhaustion. Mechanistically, we found that chronic MEK activation in T cells drove ATP demand by increasing global protein synthesis rates in vitro and in vivo. MEK inhibition reversed chronic TCR stimulation-driven increases in RNA polymerase II CTD phosphorylation, reducing transcription rates at effector- and terminal-exhaustion associated genes while maintaining transcription of memory-associated genes. These findings establish MEK-dependent metabolic demand as a driver of T cell exhaustion and elucidate the role of MEK inhibition in enhancing immunotherapy efficacy.

immunology↗

bioRxiv2023

Topographical analysis of immune cell interactions reveals a biomechanical signature for immune cytolysis

Immune cells live intensely physical lifestyles characterized by structural plasticity, mechanosensitivity, and force exertion. Whether specific immune functions require stereotyped patterns of mechanical output, however, is largely unknown. To address this question, we used super-resolution traction force microscopy to compare cytotoxic T cell immune synapses with contacts formed by other T cell subsets and macrophages. T cell synapses were globally and locally protrusive, which was fundamentally different from the coupled pinching and pulling of macrophage phagocytosis. By spectrally decomposing the force exertion patterns of each cell type, we associated cytotoxicity with compressive strength, local protrusiveness, and the induction of complex, asymmetric interfacial topographies. These features were further validated as cytotoxic drivers by genetic disruption of cytoskeletal regulators, direct imaging of synaptic secretory events, and in silico analysis of interfacial distortion. We conclude that T cell-mediated killing and, by implication, other effector responses are supported by specialized patterns of efferent force.

immunology↗

bioRxiv2022

Apoptotic contraction drives target cell release by cytotoxic T cells

Cytotoxic T lymphocytes (CTLs) use immune synapses to destroy infected or transformed target cells. Although the mechanisms governing synapse assembly have been studied extensively, little is known about how this interface dissociates, which is a critical step that both frees the CTL to search for additional prey and enables the phagocytosis of target corpses. Here, we applied time-lapse imaging to explore the basis for synapse dissolution and found that it occurred concomitantly with the cytoskeletal contraction of apoptotic targets. Genetic and pharmacological disruption of apoptotic contraction indicated that it was necessary for CTL dissociation. Furthermore, acute stimulation of contractile forces triggered the release of live targets, demonstrating that contraction is sufficient to drive the response. Finally, mechanically amplifying apoptotic contractility promoted faster CTL detachment and serial killing. Collectively, these results establish a biophysical basis for synapse dissolution and highlight the importance of mechanosensory feedback in the regulation of cell-cell interactions.

immunology↗