Persistent antigen stimulation, as observed in cancer and chronic infections, leads to T cell exhaustion (TEX), a state of impaired effector functions. Typically, TEX has been characterized by high transcriptional and epigenetic reprogramming and increased expression of inhibitory receptors, such as -cell immunoglobulin and mucin domain-3 (TIM-3), and Programmed Death-1 (PD-1). Based on the functional and epigenetic spectrum, TEX cells exist in three distinct states, namely, ‘progenitor’ (TEXprog), ‘effector-like’ (TEXeff) and ‘terminal’ (TEXterm) exhaustion states. The epigenetic stability of TEX plays a significant role in maintaining optimal control of pathogens and tumors during immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR)-T cell therapy. Besides transcriptional and epigenetic reprogramming, metabolic rewiring is also associated with T cell differentiation, including TEX.
The functional effector T cells (Teff) utilize amino acids and glucose for their growth, proliferation and effector function. TEX cells have a greater dependence on glycolysis and undergo nutrient metabolism shifts during conditions with reduced mitochondrial function. An increased uptake of oxidized lipids impairs its functional capacity. It is important to understand whether alteration in nutrient utilization in CD8+ T cells alters the epigenetic, transcriptional, and functional states throughout differentiation. Certain metabolic intermediates (e.g., acetyl-CoA) are linked with alteration of cellular epigenome. In mammalian cells, nuclear acetyl-CoA production is dependent on two enzymes, namely, acetyl-CoA synthetase 2 (ACSS2) from acetate and ATP-citrate lyase (ACLY) from citrate. Although previous studies have shown that acetyl-CoA regulates the epigenetic states and fates of CD8+ T cells, their exact mechanism of action remains elusive.
The transcriptional profiles of ACSS2 and ACLY were evaluated in CD8+ T cells isolated from tumors or acute (Armstrong) and chronic (clone 13) lymphocytic choriomeningitis virus (LCMV) infection, to explore whether selective nutrient utilization and subsequent acetyl-CoA production can regulate CD8+ T cell differentiation. To determine the key factor downstream of TCR signaling, the transcription factor NFAT was targeted, since it important to regulate CD8+ T cell activation and exhaustion. The current study explored the roles of ACSS2 and ACLY in TEX cell formation during chronic LCMV infection and tumorigenesis. The current study also investigated whether the opposite roles of ACSS2 and ACLY in murine T cells are conserved in human T cells. Furthermore, this study determined whether acetyl-CoA production downstream of specific nutrients in TEX and TEFF cells influenced histone acetylation.
The current study demonstrated that cellular nutrient preference regulates epigenetic reprogramming and cellular differentiation. It further indicated that ACSS2 and ACLY translate the cellular metabolic status of acetyl-CoA in the nucleus, which reacts with specific histone acetyltransferases (HATs) to promote histone acetylation at distinct loci, which ultimately determine CD8+ T cell fates. CD8+ T cell differentiation and function in cancer and chronic infections were found to be driven by ACSS2 and ACLY through their mutual actions with selective HATs, which helped identify the nutrients used to acetylate histones at certain loci. By translocating to the nucleus, ACSS2 and ACLY could synthesize nutrient-specific nuclear acetyl-CoA pools near specific loci. In the future, the histone code in cells can be developed in a nutrient- and locus-specific manner to manage cellular differentiation.
The current study revealed that different expressions of ACSS2 and ACLY are associated with functional effector and dysfunctional exhausted CD8+ T cells driven by chronic T cell receptor (TCR) signaling. Other data indicate that T cells alter their preference to metabolize different nutrients during prolonged antigen stimulation during the differentiation process. Notably, the findings of the current study provided a distinct target to modify nuclear acetyl-CoA metabolism to reprogram TEXterm cells to TEXprog cells epigenetically. Furthermore, the importance of selective nutrient utilization for T cell differentiation and fates was also highlighted in this study. TEXprog cell development can be effectively enhanced by targeting metabolic enzymes (e.g., ACSS2NLS) to the nucleus. This method offers a strategy for adoptive T cell transfer and CAR-T therapies. In the future, metabolic-epigenetic crosstalk linked with TEX formation such as histone lactylation, crotonylation or glycosylation should be evaluated for anti-viral and anti-tumor immunity.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Bochemistry.
Scientific references
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