Aberrant inflammation, such as that associated with inflammatory bowel disease (IBD), is fueled by the inordinate activity of RelA/NF-κB factors. As such, the canonical NF-κB module mediates controlled nuclear activation of RelA dimers from the latent cytoplasmic complexes. What provokes pathological RelA activity in the colitogenic gut remains unclear. The noncanonical NF-κB pathway typically promotes immune organogenesis involving Nfkb2 gene products. Because NF-κB pathways are intertwined, we asked whether noncanonical signaling aggravated inflammatory RelA activity. Our investigation revealed frequent engagement of the noncanonical pathway in human IBD. In a mouse model of experimental colitis, we established that Nfkb2-mediated regulations escalated the RelA-driven proinflammatory gene response in intestinal epithelial cells, exacerbating the infiltration of inflammatory cells and colon pathologies. Our mechanistic studies clarified that cell-autonomous Nfkb2 signaling supplemented latent NF-κB dimers, leading to a hyperactive canonical RelA response in the inflamed colon. In sum, the regulation of latent NF-κB dimers appears to link noncanonical Nfkb2 signaling to RelA-driven inflammatory pathologies and may provide for therapeutic targets.
Effector CD8+ T cells rely primarily on glucose metabolism to meet their biosynthetic and functional needs. However, nutritional limitations in the tumor microenvironment can cause T cell hyporesponsiveness. Therefore, T cells must acquire metabolic traits enabling sustained effector function at the tumor site to elicit a robust anti-tumor immune response. Here, we report that IL-12-stimulated CD8+ T cells have elevated intracellular acetyl CoA levels and can maintain IFNγ levels in nutrient-deprived, tumour-conditioned media (TCM). Pharmacological and metabolic analyses demonstrated an active glucose-citrate-acetyl CoA circuit in IL-12-stimulated CD8+ T cells supporting an intracellular pool of acetyl CoA in an ATP-citrate lyase (ACLY)-dependent manner. Intracellular acetyl CoA levels enhanced histone acetylation, lipid synthesis, and IFNγ production, improving the metabolic and functional fitness of CD8+ T cells in tumors. Pharmacological inhibition or genetic knockdown of ACLY severely impaired IFNγ production and viability of CD8+ T cells in nutrient-restricted conditions. Furthermore, CD8+ T cells cultured in high pyruvate-containing media in vitro acquired critical metabolic features of IL-12-stimulated CD8+ T cells and displayed improved anti-tumor potential upon adoptive transfer in murine lymphoma and melanoma models. Overall, this study delineates the metabolic configuration of CD8+ T cells required for stable effector function in tumors and presents an affordable approach to promote the efficacy of CD8+ T cells for adoptive T cell therapy.
Aberrant inflammation associated with human ailments, including inflammatory bowel disease (IBD), is typically fuelled by the inordinate activity of RelA/NF-κB transcription factors. As such, the canonical NF-κB module mediates controlled nuclear activation of RelA dimers from the latent cytoplasmic complexes. What provokes pathological RelA activity in the colitogenic gut remains unclear. The noncanonical NF-κB pathway promotes immune organogenesis involving Nfkb2 gene products. Because NF-κB pathways are intertwined, we asked if noncanonical signaling aggravated inflammatory RelA activity. Our investigation revealed frequent engagement of the noncanonical pathway in human IBD. In a mouse model, an Nfkb2 function exacerbated gut inflammation by amplifying the epithelial RelA activity induced upon intestinal injury. Our mechanistic studies clarified that cell-autonomous Nfkb2 signaling supplemented latent NF-κB dimers leading to hyperactive canonical RelA response in the inflamed colon. In sum, regulation of latent NF-κB dimers links noncanonical signaling to RelA-driven inflammatory pathologies and may provide for therapeutic targets.
<div>Abstract<p>Effector CD8<sup>+</sup> T cells rely primarily on glucose metabolism to meet their biosynthetic and functional needs. However, nutritional limitations in the tumor microenvironment can cause T-cell hyporesponsiveness. Therefore, T cells must acquire metabolic traits enabling sustained effector function at the tumor site to elicit a robust antitumor immune response. Here, we report that IL12-stimulated CD8<sup>+</sup> T cells have elevated intracellular acetyl CoA levels and can maintain IFNγ levels in nutrient-deprived, tumor-conditioned media (TCM). Pharmacological and metabolic analyses demonstrated an active glucose–citrate–acetyl CoA circuit in IL12-stimulated CD8<sup>+</sup> T cells supporting an intracellular pool of acetyl CoA in an ATP-citrate lyase (ACLY)–dependent manner. Intracellular acetyl CoA levels enhanced histone acetylation, lipid synthesis, and IFNγ production, improving the metabolic and functional fitness of CD8<sup>+</sup> T cells in tumors. Pharmacological inhibition or genetic knockdown of ACLY severely impaired IFNγ production and viability of CD8<sup>+</sup> T cells in nutrient-restricted conditions. Furthermore, CD8<sup>+</sup> T cells cultured in high pyruvate–containing media <i>in vitro</i> acquired critical metabolic features of IL12-stimulated CD8<sup>+</sup> T cells and displayed improved antitumor potential upon adoptive transfer in murine lymphoma and melanoma models. Overall, this study delineates the metabolic configuration of CD8<sup>+</sup> T cells required for stable effector function in tumors and presents an affordable approach to promote the efficacy of CD8<sup>+</sup> T cells for adoptive T-cell therapy.</p>Significance:<p>IL12-mediated metabolic reprogramming increases intracellular acetyl CoA to promote the effector function of CD8<sup>+</sup> T cells in nutrient-depleted tumor microenvironments, revealing strategies to potentiate the antitumor efficacy of T cells.</p></div>
Supplementary Data from Intracellular Acetyl CoA Potentiates the Therapeutic Efficacy of Antitumor CD8<sup>+</sup> T Cells
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