Stewart, K. M. | Search bioRxiv

bioRxiv2025

Methionine regulates antitumor function of CD8⁺ T cells through polyamine synthesis

Methionine is an essential amino acid critical for T cell activation. While methionine restriction (MR) combined with immune checkpoint blockade has been shown to enhance T cell function, the impact of methionine on adoptive T cell therapies is largely unexplored. Here, we examined the functionality of T cells under MR and pharmaceutical inhibition of the methionine cycle (MAT2Ai), using primary T cells and a murine adoptive T cell therapy model. In vitro, transient MR or MAT2Ai treatment increased interferon gamma (IFN{gamma}) expression in CD8+ T cells, whereas sustained MR led to the upregulation of T cell exhaustion-associated markers. Mechanistically, transient MR suppressed the polyamine synthesis pathway, and supplementation with polyamines reversed MR-induced IFN{gamma} expression. Genetic ablation of s-adenosylmethionine decarboxylase, an enzyme in the polyamine synthesis pathway, recapitulated the effect of MR, indicating that transient MR enhances T cell function by inhibiting polyamine synthesis. Despite this, transient MR treatment of ovalbumin (OVA)-specific (OT-I) CD8+ T cells prior to adoptive transfer did not improve antitumor efficacy against EG7-OVA tumors in vivo. In contrast, sustained dietary MR accelerated EG7-OVA tumor growth in mice treated with OT-I T cells, demonstrating that methionine availability is essential for the activity of adoptively transferred T cells. These findings suggest that enhancing methionine availability in the tumor microenvironment may improve the efficacy of adoptive T cell therapies.

immunology↗

bioRxiv2021

A seasonal pulse of ungulate neonates influences space use by carnivores in a multi-predator, multi-prey system

O_LIThe behavioral mechanisms by which predators encounter prey are poorly resolved. In particular, the extent to which predators engage in active search for prey versus incidentally encountering them is unknown. The distinction between search and incidental encounter influences prey population dynamics with active search exerting a stabilizing force on prey populations by alleviating predation pressure on low-density prey and increasing it for high-density prey. C_LIO_LIParturition of many large herbivores occurs during a short and predictable temporal window in which young are highly vulnerable to predation. Our study aims to determine how a suite of carnivores responds to the seasonal pulse of newborn ungulates using contemporaneous GPS locations of four species of predators and two species of prey. C_LIO_LIWe used step-selection functions to assess whether coyotes, cougars, black bears, and bobcats actively searched for parturient females in a low-density population of mule deer and a high-density population of elk. We then assessed whether searching carnivores shifted their habitat use toward areas exhibiting a high probability of encountering neonates. C_LIO_LINone of the four carnivore species encountered parturient mule deer more often than expected by chance suggesting that predation of young resulted from incidental encounters. By contrast, we determined that cougar and male bear movements positioned them in proximity of parturient elk more often than expected by chance which is evidence of searching behavior. Although both male bears and cougars searched for neonates, only male bears used elk parturition habitat in a way that dynamically tracked the phenology of the elk birth pulse suggesting that maximizing encounters with juvenile elk was a motivation when selecting resources. C_LIO_LIOur results support the existence of a stabilizing mechanism to prey populations through active search behavior by predators because carnivores in our study searched for the high-density prey species (elk) but ignored the low-density species (mule deer). We conclude that prey density must be high enough to warrant active search, and that there is high interspecific and intersexual variability in foraging strategies among large mammalian predators and their prey. C_LI

ecology↗