Nutrient metabolism regulates T cell depletion and therapeutic potential

By establishing a new link between cellular nutrition and identity, scientists have shown that targeting nutrient-dependent activities could lead to improved immunotherapy.

study: Nutrient-induced histone code determines depleted CD8⁺ T cell fate. Image credit: Nemes Laszlo/Shutterstock.com

recent science The study investigated how nuclear metabolic enzymes establish a link between locus-specific epigenetic reprogramming. T cells and nutrient availability.

Relationship between T cell depletion and nutrients

sustained antigen As observed in cancer and chronic infections, stimulation leads to T cell exhaustion (TEX), a state in which effector function is impaired. Generally, TEX is characterized by advanced transcriptional and epigenetic reprogramming and increased expression of inhibitory receptors such as cellular immunoglobulin and mucin domain 3 (TIM-3) and programmed death 1 (PD-1). You can

Based on their functional and epigenetic spectrum, TEX cells exist in three distinct states: “progenitor” (TEXprog), “effector-like” (TEXeff), and “terminus” (TEXterm) depleted. .

The epigenetic stability of TEX plays a critical role in maintaining optimal control of pathogens and tumors during immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR)-T cell therapy. In addition to transcriptional and epigenetic reprogramming, metabolic rewiring is also associated with T cell differentiation, including TEX.

Functional effector T cells (TEFFs) utilize amino acids and glucose for growth, proliferation, and effector functions. TEX cells are highly dependent on glycolysis, and altered nutrient metabolism occurs when mitochondrial function is impaired.

Increased uptake of oxidized lipids impairs their functional capacity. It is important to understand whether changes in nutrient availability in CD8+ T cells alter epigenetic, transcriptional, and functional states throughout differentiation.

Certain metabolic intermediates (such as acetyl-CoA) are associated with changes in the cellular epigenome. In mammalian cells, nuclear acetyl-CoA production relies on two enzymes: acetyl-CoA synthetase 2 from acetate (ACSS2) and ATP citrate lyase from citrate (ACLY).

Previous studies have shown that nuclear acetyl-CoA regulates the epigenetic state and fate of CD8+ T cells, but its precise mechanism of action remains unclear.

About research

Transcriptional profiles of ACSS2 and ACLY were analyzed in tumors or in acute (Armstrong) and chronic (Clone 13) lymphocytic choroidal medulla to investigate whether selective nutrient utilization and subsequent acetyl-CoA production can control CD8+. was evaluated in CD8+ T cells isolated from LCMV infection. T cell differentiation.

To determine the key factors downstream of TCR signaling, nuclear factor of activated T cells (NFAT) was targeted. It is an important transcription factor that controls the activation and depletion of CD8+ T cells.

In the current study, we investigated the role of ACSS2 and ACLY in TEX cell formation during chronic LCMV infection and tumorigenesis. For this, single guide (sg) RNA containing Cas9 ribonucleoprotein (RNP) (CRISPR-Cas9/RNP) was used by electroporation to extract ACSS2 and Removed ACLY.

In this study, we also investigated whether the opposing roles of ACSS2 and ACLY in mouse T cells are conserved in human T cells. Additionally, this study determined whether acetyl-CoA production downstream of specific nutrients in TEX and TEFF cells affects histones. Acetylation.

Research results

This study demonstrated that cellular nutrient preferences control epigenetic reprogramming and cell differentiation.

Furthermore, ACSS2 and ACLY translate the cellular metabolic status of acetyl-CoA in the nucleus and react with specific histone acetyltransferases (HATs) to promote histone acetylation at different loci, ultimately promoting CD8+ T cell It was shown to determine fate.

D8+ T cell differentiation and function in cancer and chronic infections were found to be driven by ACSS2 and ACLY through interaction with selective HATs. This helped identify the nutrients used to acetylate histones at specific loci.

By translocating to the nucleus, ACSS2 and ACLY were able to synthesize nutrient-specific nuclear acetyl-CoA pools near specific genetic loci. In the future, the intracellular histone code will be developed in a nutrient- and locus-specific manner to manage cell differentiation.

This study reveals that differential expression of ACSS2 and ACLY is associated with functional effectors driven by chronic T cell receptor (TCR) signaling and dysfunctionally exhausted CD8+ T cells. .

Experimental results show that prolonged antigen stimulation during the differentiation process changes T cells' preferences for metabolizing different nutrients.

conclusion

Remarkably, the results of the present study provided a clear target to epigenetically reprogram TEXterm cells into TEXprog cells by altering nuclear acetyl-CoA metabolism. Additionally, this study also highlighted the importance of selective nutrient availability for T cell differentiation and fate.

TEXprog cell development can be effectively promoted by targeting metabolic enzymes (such as ACSS2NLS) to the nucleus. This method provides a strategy for adoptive T cell transfer and CAR-T therapy.

In the future, metabolic epigenetic crosstalk associated with TEX formation, including histone crotonylation, histone glycosylation, and histone lactylation, should be evaluated for antiviral and antitumor immunity.

Environmental factors that may influence metabolic enzymes with respect to epigenetic changes due to specific nutrients also need to be investigated in the future.