Journal of immunology (Baltimore, Md. : 1950)Oct 13, 2026

CRISPR-Cas9 screen finds eIF4G2 controls CD8+ T cell dysfunction

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 14, 2026

Abstract

Deletion of eIF4G2 in CD8+ T cells restores their survival and proliferation during chronic stimulation.

Chronic antigen exposure can lead to CD8+ T cell dysfunction, characterized by impaired proliferation and increased inhibitory receptors.
A murine ex vivo model was developed to study CD8+ T cell dysfunction in a controlled environment.
eIF4G2, a noncanonical mRNA translation factor, is necessary for the progression of CD8+ T cells to a dysfunctional state.
Removing eIF4G2 reversed the dysfunctional state, promoting a shift to a more proliferative phenotype.
eIF4G2 depletion also decreased oxidative stress and misfolded protein accumulation in CD8+ T cells.
Enhanced tumor control was observed in eIF4G2-depleted CD8+ T cells in a melanoma model.

Simplified

CD8+ T cells directly target and kill cancer cells and are required for effective antitumor immunity. However, CD8+ T cells may become dysfunctional when exposed to chronic antigen stimulation during cancer. Dysfunction is characterized by reduced proliferation, increased expression of inhibitory receptors, and impaired effector function, yet the genetic mechanisms controlling dysfunction remain poorly understood. Therefore, we developed a murine ex vivo chronic stimulation model that recapitulates features of CD8+ T cell dysfunction observed within the tumor microenvironment. By coupling this system with genome-wide CRISPR-Cas9 loss-of-function screening, we discovered that the progression of murine CD8+ T cells to a dysfunctional state required eIF4G2, a noncanonical mRNA translation factor. Deletion of eIF4G2 restored CD8+ T cell survival and proliferation during chronic stimulation conditions in vitro. Transcriptomic, proteomic, and flow cytometric analyses revealed that eIF4G2 deletion shifts CD8+ T cell phenotype from a dysfunctional state to a proliferative state. eIF4G2 depletion reduced oxidative stress, lipid peroxidation, and accumulation of misfolded protein aggresomes during chronic in vitro stimulation. Finally, eIF4G2-depleted cells mediated enhanced tumor control in a murine model of melanoma. These data suggest that targeting eIF4G2 may promote CD8+ T cell resilience and improve therapeutic antitumor immunity.

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CRISPR-Cas9 screen finds eIF4G2 controls CD8+ T cell dysfunction

Abstract

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