Naive CD8 + T cells rely upon oxidation of fatty acids as a primary source of energy. After antigen encounter, T cells shift to a glycolytic metabolism to sustain effector function. It is unclear, however, whether changes in glucose metabolism ultimately influence the ability of activated T cells to become long-lived memory cells. We used a fluorescent glucose analog, 2-NBDG, to quantify glucose uptake in activated CD8 + T cells. We found that cells exhibiting limited glucose incorporation had a molecular profile characteristic of memory precursor cells and an increased capacity to enter the memory pool compared with cells taking up high amounts of glucose. Accordingly, enforcing glycolytic metabolism by overexpressing the glycolytic enzyme phosphoglycerate mutase-1 severely impaired the ability of CD8 + T cells to form long-term memory. Conversely, activation of CD8 + T cells in the presence of an inhibitor of glycolysis, 2-deoxyglucose, enhanced the generation of memory cells and antitumor functionality. Our data indicate that augmenting glycolytic flux drives CD8 + T cells toward a terminally differentiated state, while its inhibition preserves the formation of long-lived memory CD8 + T cells. These results have important implications for improving the efficacy of T cell-based therapies against chronic infectious diseases and cancer.
Tumours progress despite being infiltrated by tumour-specific effector T cells1. Tumours contain areas of cellular necrosis, which is associated with poor survival in a variety of cancers2. Here, we show that necrosis releases an intracellular ion, potassium, into the extracellular fluid of mouse and human tumours causing profound suppression of T cell effector function. We find that elevations in the extracellular potassium concentration [K + ]e act to impair T cell receptor (TCR)-driven Akt-mTOR phosphorylation and effector programmes, this potassium-mediated suppression of Akt-mTOR signalling and T cell function is dependent upon the activity of the serine/threonine phosphatase PP2A3,4. While the suppressive effect mediated by elevated [K + ]e is independent of changes in plasma membrane potential (V m ), it does require an increase in intracellular potassium ([K + ]i). Concordantly, ionic reprogramming of tumour-specific T cells through overexpression of the potassium channel K v 1.3 lowers [K + ]i and improves effector Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use
Th17 cells have been described as short-lived but this view is at odds with their capacity to trigger protracted damage to normal and transformed tissues. We report that Th17 cells, despite displaying low expression of CD27 and other phenotypic markers of terminal differentiation, efficiently eradicated tumors and caused autoimmunity, were long-lived and maintained a core molecular signature resembling early memory CD8+ cells with stem cell-like properties. In addition, we found that Th17 cells had high expression of Tcf7, a direct target of the Wnt and β-catenin signaling axis, and accumulated β-catenin, a feature observed in stem cells. In vivo, Th17 cells gave rise to Th1-like effector cell progeny and also self-renewed and persisted as IL-17A-secreting cells. Multipotency was required for Th17 cell-mediated tumor eradication because effector cells deficient in IFN-γ or IL-17A had impaired activity. Thus, Th17 cells are not always short-lived and are a less-differentiated subset capable of superior persistence and functionality.
Through their functional diversification, distinct lineages of CD4+ T cells play key roles in either driving or constraining immune-mediated pathology. Transcription factors are critical in the generation of cellular diversity, and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage commitment1. Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma2, Crohn’s disease3–4, coeliac disease5, vitiligo6, multiple sclerosis7 and type 1 diabetes8. While these associations point to a shared mechanism underlying susceptibility to diverse immune-mediated diseases, a function for Bach2 in the maintenance of immune homeostasis has not been established. Here, we define Bach2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programmes of multiple effector lineages in CD4+ T cells. Bach2 was required for efficient formation of regulatory (Treg) cells and consequently for suppression of lethal inflammation in a manner that was Treg cell dependent. Assessment of the genome-wide function of Bach2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during Treg polarization resulted in inappropriate diversion to effector lineages. In addition, Bach2 constrained full effector differentiation within Th1, Th2 and Th17 cell lineages. These findings identify Bach2 as a key regulator of CD4+ T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity.
Enhancers regulate spatiotemporal gene expression and impart cell-specific transcriptional outputs that drive cell identity1. Stretch- or super-enhancers (SEs) are a subset of enhancers especially important for genes associated with cell identity and genetic risk of disease2,3,4,5,6. CD4+ T cells are critical for host defense and autoimmunity. Herein, we analyzed maps of T cell SEs as a non-biased means of identifying key regulatory nodes involved in cell specification. We found that cytokines and cytokine receptors were the dominant class of genes exhibiting SE architecture in T cells. This notwithstanding, the locus encoding Bach2, a key negative regulator of effector differentiation, emerged as the most prominent T cell SE, revealing a network wherein SE-associated genes critical for T cell biology are repressed by BACH2. Disease-associated SNPs for immune-mediated disorders, including rheumatoid arthritis (RA), were highly enriched for T cell-SEs versus typical enhancers (TEs) or SEs in other cell lineages7. Intriguingly, treatment of T cells with the Janus kinase (JAK) inhibitor, tofacitinib, disproportionately altered the expression of RA risk genes with SE structures. Together, these results indicate that genes with SE architecture in T cells encompass a variety of cytokines and cytokine receptors but are controlled by a “guardian” transcription factor, itself endowed with an SE. Thus, enumeration of SEs allows unbiased determination of key regulatory nodes in T cells, which are preferentially modulated by pharmacological intervention.
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