The DOI matches its Crossref record; 16 of the 16 references it cites were found in a registry or an index.
Leptin Metabolically Licenses T Cells for Activation To Link Nutrition and Immunity
Open accessAbstract
Immune responses are highly energy-dependent processes. Activated T cells increase glucose uptake and aerobic glycolysis to survive and function. Malnutrition and starvation limit nutrients and are associated with immune deficiency and increased susceptibility to infection. Although it is clear that immunity is suppressed in times of nutrient stress, mechanisms that link systemic nutrition to T cell function are poorly understood. We show in this study that fasting leads to persistent defects in T cell activation and metabolism, as T cells from fasted animals had low glucose uptake and decreased ability to produce inflammatory cytokines, even when stimulated in nutrient-rich media. To explore the mechanism of this long-lasting T cell metabolic defect, we examined leptin, an adipokine reduced in fasting that regulates systemic metabolism and promotes effector T cell function. We show that leptin is essential for activated T cells to upregulate glucose uptake and metabolism. This effect was cell intrinsic and specific to activated effector T cells, as naive T cells and regulatory T cells did not require leptin for metabolic regulation. Importantly, either leptin addition to cultured T cells from fasted animals or leptin injections to fasting animals was sufficient to rescue both T cell metabolic and functional defects. Leptin-mediated metabolic regulation was critical, as transgenic expression of the glucose transporter Glut1 rescued cytokine production of T cells from fasted mice. Together, these data demonstrate that induction of T cell metabolism upon activation is dependent on systemic nutritional status, and leptin links adipocytes to metabolically license activated T cells in states of nutritional sufficiency.
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Citations
Cites
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197
Adipokines in inflammation and metabolic disease
Ouchi, N., Parker, J. L., Lugus, J. J., & Walsh, K. (2011) · Nature Reviews Immunology · doi:10.1038/nri2921 · Cited by 4,625
Inflammatory Mechanisms in Obesity
Gregor, M. F., & Hotamisligil, G. S. (2011) · Annual Review of Immunology · doi:10.1146/annurev-immunol-031210-101322 · Cited by 3,754
Role of leptin in the neuroendocrine response to fasting
Ahima, R. S., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., Maratos-Flier, E., & Flier, J. S. (1996) · Nature · doi:10.1038/382250a0 · Cited by 3,117
The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation
Wang, R., Dillon, C. P., Shi, L. Z., Milasta, S., Carter, R., Finkelstein, D., McCormick, L. L., Fitzgerald, P., Chi, H., Munger, J., et al. (2011) · Immunity · doi:10.1016/j.immuni.2011.09.021 · Cited by 2,140 · cited 2×
“It has recently been demonstrated that regulatory pathways controlling T cell metabolism are intimately linked to T cell function (4, 6, 7).”
BackgroundMichalek, R. D., Gerriets, V. A., Jacobs, S. R., Macintyre, A. N., MacIver, N. J., Mason, E. F., Sullivan, S. A., Nichols, A. G., & Rathmell, J. C. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003613 · Cited by 2,091
Self-citationShi, L. Z., Wang, R., Huang, G., Vogel, P., Neale, G., Green, D. R., & Chi, H. (2011) · Journal of Experimental Medicine · doi:10.1084/jem.20110278 · Cited by 1,803
The CD28 Signaling Pathway Regulates Glucose Metabolism
Frauwirth, K. A., Riley, J. L., Harris, M. H., Parry, R. V., Rathmell, J. C., Plas, D. R., Elstrom, R. L., June, C. H., & Thompson, C. B. (2002) · Immunity · doi:10.1016/s1074-7613(02)00323-0 · Cited by 1,475 · cited 1×
“This is also consistent with previous reports that CD28 costimulation is required for increased glycolysis in activation (61).”
ResultSelf-citationMetabolic Regulation of T Lymphocytes
MacIver, N. J., Michalek, R. D., & Rathmell, J. C. (2013) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032712-095956 · Cited by 1,244
Self-citationFeast and Famine: Critical Role of Glucocorticoids with Insulin in Daily Energy Flow
Dallman, M. F., Strack, A. M., Akana, S. F., Bradbury, M. J., Hanson, E. S., Scribner, K. A., & Smith, M. (1993) · Frontiers in Neuroendocrinology · doi:10.1006/frne.1993.1010 · Cited by 796 · cited 1×
“Fasting has a number of important systemic effects, including increasing circulating levels of glucocorticoids (62, 63), which have potent effects on lymphocyte survival and function.”
Background
Cited by
Popkin, B. M., Du, S., Green, W. D., Beck, M. A., Algaith, T., Herbst, C. H., Alsukait, R. F., Alluhidan, M., Alazemi, N., & Shekar, M. (2020) · Obesity Reviews · doi:10.1111/obr.13128 · Cited by 1,150
Wang, Z., Aguilar, E. G., Luna, J. I., Dunai, C., Khuat, L. T., Le, C. T., Mirsoian, A., Minnar, C. M., Stoffel, K. M., Sturgill, I. R., et al. (2019) · Nature Medicine · doi:10.1038/s41591-018-0221-5 · Cited by 865
Metabolic Regulation of T Cell Longevity and Function in Tumor Immunotherapy
Kishton, R. J., Sukumar, M., & Restifo, N. P. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.06.016 · Cited by 548
Changes in Nutritional Status Impact Immune Cell Metabolism and Function
Alwarawrah, Y., Kiernan, K., & MacIver, N. J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01055 · Cited by 513
Self-citationObesity, Fat Mass and Immune System: Role for Leptin
Francisco, V., Pino, J., Campos-Cabaleiro, V., Ruiz-Fernández, C., Mera, A., Gonzalez-Gay, M. A., Gómez, R., & Gualillo, O. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00640 · Cited by 411
Metadata
- Authors
- Saucillo, D. C., Gerriets, V. A., Sheng, J., Rathmell, J. C., & MacIver, N. J.
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-01-01
- Volume
- 192
- Issue
- 1
- Pages
- 136-144
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2117971406
- Cited by
- 282
- References
- 16
- FWCI
- 4.88
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Saucillo, D. C., Gerriets, V. A., Sheng, J., Rathmell, J. C., & MacIver, N. J. (2014). Leptin Metabolically Licenses T Cells for Activation To Link Nutrition and Immunity. The Journal of Immunology. https://doi.org/10.4049/jimmunol.1301158
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Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
