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RNA-seq of mouse Pmel-1 CD8 T cell with Ucp2 inhibition and NAC treatment

ABSTRACT: Enhanced T cell stemness and anti-tumor activity of adoptively transferred T cells are linked to T cell metabolism, however, the mitochondrial regulation of T-cell longevity and anti-tumor activity remains elusive. Here, using loss and gain of function experiments, we show that a mitochondrial inner membrane protein, Uncoupling protein 2 (Ucp2), is required for T cell longevity and anti-tumor function. Loss of mitochondrial Ucp2 activity in T cells results in accelerated differentiation into ‘terminal effector cells’. We found that Ucp2 modulate oxidative stress and DNA damage by regulating the levels of mitochondrial superoxide. We observed that reducing mitochondrial ROS was sufficient to rescue the loss of Ucp2-mediated increase in effector T cell differentiation, senescence, cytokine production and anti-tumor activity. Tumor-specific CD8+ T cells could be metabolically reprogrammed by increasing Ucp2 levels and Ucp2-overexpressing T cells displayed long-term survival and restricted tumor growth and prolonged the survival of melanoma-bearing mice. Our results establish a novel role of Ucp2 in regulating T cell longevity and anti-tumor activity by repressing mitochondrial dysfunction and suggest that manipulating Ucp2 levels in T cells should enhance T cell-based immunotherapies for cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE171477 | GEO | 2021/06/15

REPOSITORIES: GEO

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Expression data for naÃ¯ve IL-2 and IL-12 primed Pmel-1 CD8+ T-cells

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