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Targeting UBE2F induces a resilience program enhancing CD8 T cell immunity [Bulk RNA-seq]

ABSTRACT: CD8 memory T cells (TMEM) and exhausted T cells (TEX) are essential for host defense against infection and cancer, yet their therapeutic potential is often limited by insufficient persistence and sustained functional capacity. Strategies to enhance the longevity of both populations remain scarce. Here, we demonstrate that ablation of UBE2F, a neddylation E2 enzyme, induces a resilience program in CD8 T cells that operates across both TMEM and TEX compartments, resulting in improved viral and tumor control. This resilience state is characterized by enhanced self-renewal and survival without perturbing the conventional CD8 T cell differentiation trajectories. Mechanistically, UBE2F deficiency inhibited neddylation of CUL5, leading to accumulation of JUNB and upregulation of IL-2Rβ. The increased IL-2Rβ expression hypersensitizes CD8 T cells to physiological IL-15, thereby conferring the resilience features. Together, these findings identify the UBE2F-CUL5-JUNB-IL-2Rβ axis as a conserved post-translational mechanism regulating CD8 T cell longevity across memory and exhausted states, providing a novel strategy for enhancing antiviral and antitumor immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE327640 | GEO | 2026/04/15

REPOSITORIES: GEO

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Project description:Some unicellular organisms exhibit collective decision-making through intercellular communication once a quorum of members sense an environmental stress. Whether T cells at different states of differentiation may also synchronize their behavior on a population basis through direct interactions remains unclear. We report that memory CD8+ T cells (TMem) directly interact with naive T cells (TN) during priming, affecting the phenotypic, functional, transcriptional and metabolic differentiation of TN-derived progeny. This previously unrecognized, contact and concentration-dependent interaction between naive (TN) and memory CD8+ T cells (TMem) directly enhanced TN effector differentiation through non-apoptotic Fas signaling resulting in downstream Akt pathway activation. TN primed with TMem exhibited significantly impaired persistence and antitumor activity compared with TN primed alone. Disruption of FasL-Fas signaling in TN cells limited differentiation and enhanced anti-tumor immunity while provision of exogenous FasL in the absence of TMem impaired anti-tumor immunity by augmenting TN differentiation. These findings reveal that the full therapeutic potential of TN-derived cells for adoptive immunotherapy requires physical separation from TMem prior to priming or antagonism of Fas-signaling. FACS-sorted in vitro differentiated TMem samples were without stimulation (0 hours) (n=3), and FACS-sorted in vitro differentiated TMem samples were stimulated using CD3-specific and CD28-specific antibodies and IL-2 for 18 (n=3) and 96 (n=3) hours. FACS-sorted naive Pmel-1 CD8+ T cell samples were without stimulation (0 hours) (n=3), and FACS-sorted TN-derived Pmel-1 CD8+ T cell samples were stimulated using CD3-specific and CD28-specific antibodies and IL-2 for 18 (n=3) and 96 (n=3) hours. FACS-sorted TN-derived Pmel-1 CD8+ T cell samples were stimulated in the presence of TMem using CD3-specific and CD28-specific antibodies and IL-2 for 18 (n=3) and 96 (n=3) hours. FACS-sorted in vitro differentiated TMem samples were stimulated in the presence of TN using CD3-specific and CD28-specific antibodies and IL-2 for 18 (n=3) and 96 (n=3) hours. All samples were done in triplicate as biological repeats.

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Targeting UBE2F induces a resilience program enhancing CD8 T cell immunity [Bulk RNA-seq]

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