Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1
| Autor: | Che-Ping Ng, Philip A. Hull, Mingjian Fei, Mark Y. Jeng, Hye-Sook Kwon, Nevan J. Krogan, Herb Kasler, Jeffrey R. Johnson, Melanie Ott, Eric Verdin, Chia-Lin Tsou, David E. Gordon |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Granzyme B production Cytotoxicity Immunologic endocrine system Cytotoxicity Immunology chemical and pharmacologic phenomena CD8-Positive T-Lymphocytes Medical and Health Sciences 03 medical and health sciences Sirtuin 1 CD28 Antigens T-Lymphocyte Subsets Immunologic medicine Immunology and Allergy Cytotoxic T cell Humans 2.1 Biological and endogenous factors Aetiology Research Articles Regulation of gene expression Chemistry Forkhead Box Protein O1 Prevention Brief Definitive Report CD28 food and beverages hemic and immune systems 3. Good health Cell biology 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation lipids (amino acids peptides and proteins) NAD+ kinase Energy Metabolism Memory T cell Reprogramming Immunologic Memory CD8 hormones hormone substitutes and hormone antagonists Biomarkers |
| Zdroj: | The Journal of experimental medicine, vol 215, iss 1 The Journal of Experimental Medicine |
| Popis: | The evolutionarily conserved SIRT1–FoxO1 axis plays a new role in human CD8+ T cell metabolism and function. Progression from the naive to the terminally differentiated memory state is accompanied by the loss of SIRT1 and FoxO1 expression, which derepresses glycolytic and cytotoxic capacities of CD8+CD28– T cells under resting conditions. The expansion of CD8+CD28– T cells, a population of terminally differentiated memory T cells, is one of the most consistent immunological changes in humans during aging. CD8+CD28– T cells are highly cytotoxic, and their frequency is linked to many age-related diseases. As they do not accumulate in mice, many of the molecular mechanisms regulating their fate and function remain unclear. In this paper, we find that human CD8+CD28– T cells, under resting conditions, have an enhanced capacity to use glycolysis, a function linked to decreased expression of the NAD+-dependent protein deacetylase SIRT1. Global gene expression profiling identified the transcription factor FoxO1 as a SIRT1 target involved in transcriptional reprogramming of CD8+CD28– T cells. FoxO1 is proteasomally degraded in SIRT1-deficient CD8+CD28– T cells, and inhibiting its activity in resting CD8+CD28+ T cells enhanced glycolytic capacity and granzyme B production as in CD8+CD28– T cells. These data identify the evolutionarily conserved SIRT1–FoxO1 axis as a regulator of resting CD8+ memory T cell metabolism and activity in humans. |
| Databáze: | OpenAIRE |
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