The transcription factor Bhlhe40 programs mitochondrial regulation of resident CD8+ T cell fitness and functionality
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE135278 | GEO | 2019/09/17
REPOSITORIES: GEO
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Project description:Tissue-resident memory CD8 T cells (TRM) offer fast, robust, and long-term protection at sites of re-infection1. Tumor-infiltrating lymphocytes (TIL) with characteristics of TRM maintain enhanced effector functions, predict responses to immunotherapy, and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency could inform new approaches to empower T cell responses in tissues and solid tumors. To systematically define the basis for the metabolic reprogramming supporting TRM differentiation, survival, and function, we leveraged in vivo functional genomics, untargeted metabolomics, and transcriptomics of virus-specific memory CD8 T cell populations. We found that memory CD8 T cells deployed a range of adaptations to tissue residency, including a marked reliance on non-steroidal products of the mevalonate/cholesterol pathway, such as Coenzyme Q (CoQ), driven by increased activity of the transcription factor Srebp2. This metabolic adaptation was most pronounced in the small intestine (SI), where TRM interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional TIL in diverse tumor types in mice and humans. Enforcing CoQ synthesis through Fdft1 deletion or Pdss2 overexpression promoted mitochondrial respiration, memory formation upon viral infection, and enhanced antitumor immunity. In sum, through a systematic exploration of TRM metabolism, we reveal how these programs can be leveraged to empower CD8 T cell memory formation in the context of acute infections and enhance antitumor immunity.
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Project description:Tissue-resident memory CD8 T cells (TRM) offer fast, robust, and long-term protection at sites of re-infection1. Tumor-infiltrating lymphocytes (TIL) with characteristics of TRM maintain enhanced effector functions, predict responses to immunotherapy, and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency could inform new approaches to empower T cell responses in tissues and solid tumors. To systematically define the basis for the metabolic reprogramming supporting TRM differentiation, survival, and function, we leveraged in vivo functional genomics, untargeted metabolomics, and transcriptomics of virus-specific memory CD8 T cell populations. We found that memory CD8 T cells deployed a range of adaptations to tissue residency, including a marked reliance on non-steroidal products of the mevalonate/cholesterol pathway, such as Coenzyme Q (CoQ), driven by increased activity of the transcription factor Srebp2. This metabolic adaptation was most pronounced in the small intestine (SI), where TRM interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional TIL in diverse tumor types in mice and humans. Enforcing CoQ synthesis through Fdft1 deletion or Pdss2 overexpression promoted mitochondrial respiration, memory formation upon viral infection, and enhanced antitumor immunity. In sum, through a systematic exploration of TRM metabolism, we reveal how these programs can be leveraged to empower CD8 T cell memory formation in the context of acute infections and enhance antitumor immunity.
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