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Targeting UBE2F induces a resilience program enhancing CD8 T cell immunity

Xiaonan Ma1,2,3,4, Henan Guo1,2,3, Yuting Jia2

  • 1State Key Laboratory of Molecular Oncology, Institute for Immunology, Beijing Key Laboratory for Mechanisms and Drug Development of Allergic Diseases, School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University , Beijing, China.

The Journal of Experimental Medicine
|May 26, 2026
PubMed

Insights

Ablating UBE2F, a neddylation enzyme, enhances CD8 T cell resilience and longevity. This improves immune responses against viruses and tumors by boosting self-renewal and survival.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Memory CD8 T cells (TMEM) and exhausted CD8 T cells (TEX) are crucial for fighting infections and cancer.
  • Their therapeutic use is limited by poor persistence and sustained function.
  • Effective strategies to prolong CD8 T cell longevity are scarce.

Purpose of the Study:

  • To investigate the role of UBE2F in CD8 T cell longevity.
  • To identify mechanisms for enhancing CD8 T cell persistence and function.
  • To explore novel strategies for improving antiviral and antitumor immunity.

Main Methods:

  • Utilized gene ablation of UBE2F in CD8 T cells.
  • Analyzed CD8 T cell resilience, self-renewal, and survival.
  • Investigated the UBE2F-CUL5-JUNB-IL-2Rβ signaling axis.
  • Assessed viral and tumor control in vivo.

Main Results:

  • UBE2F ablation induced a resilience program in both TMEM and TEX cells.
  • This resilience enhanced CD8 T cell self-renewal and survival without altering differentiation.
  • Mechanistically, UBE2F deficiency inhibited CUL5 neddylation, increasing JUNB and IL-2Rβ.
  • Increased IL-2Rβ sensitized cells to IL-15, conferring resilience and improving host defense.

Conclusions:

  • UBE2F is a key regulator of CD8 T cell longevity across memory and exhausted states.
  • The UBE2F-CUL5-JUNB-IL-2Rβ pathway offers a novel target for enhancing T cell-based immunotherapies.
  • This strategy holds promise for improving outcomes in viral infections and cancer treatment.

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