Insulin Receptor-Mediated Stimulation Boosts T Cell Immunity during Inflammation and Infection
Open accessAbstract
T cells represent a critical effector of cell-mediated immunity. Activated T cells engage in metabolic reprogramming during effector differentiation to accommodate dynamic changes in energy demands. Here, we show that the hormone, insulin, and downstream signaling through its insulin receptor shape adaptive immune function through modulating T cell metabolism. T cells lacking insulin receptor expression (LckCre+ Insr fl/fl) show reduced antigen-specific proliferation and compromised production of pro-inflammatory cytokines. In vivo, T cell-specific insulin receptor deficiency reduces T cell-driven colonic inflammation. In a model of severe influenza infection with A/PR8 (H1N1), lack of insulin receptor on T cells curtails antigen-specific immunity to influenza viral antigens. Mechanistically, insulin receptor signaling reinforces a metabolic program that supports T cell nutrient uptake and associated glycolytic and respiratory capacities. These data highlight insulin receptor signaling as an important node integrating immunometabolic pathways to drive optimal T cell effector function in health and disease.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Insulin is a critical mediator of adaptive immune effector function against respiratory infections.
“Insulin is a critical mediator of adaptive immune effector function against respiratory infections172, and mTORC1 activation of S6 kinase blocks insulin signaling173,174.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [172]
Cites
Molecular mechanisms of T cell co-stimulation and co-inhibition
Chen, L., & Flies, D. B. (2013) · Nature Reviews Immunology · doi:10.1038/nri3405 · Cited by 3,114 · see citing works
Critical nodes in signalling pathways: insights into insulin action
Taniguchi, C. M., Emanuelli, B., & Kahn, C. R. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1837 · Cited by 2,760 · see citing works
Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis
Chang, C.-H., Curtis, J. D., Maggi, L. B., Faubert, B., Villarino, A. V., O’Sullivan, D., Huang, S. C.-C., van der Windt, G. J. W., Blagih, J., Qiu, J., et al. (2013) · Cell · doi:10.1016/j.cell.2013.05.016 · Cited by 2,204 · see citing works
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 · see citing works
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 · see citing works
Sena, L. A., Li, S., Jairaman, A., Prakriya, M., Ezponda, T., Hildeman, D. A., Wang, C.-R., Schumacker, P. T., Licht, J. D., Perlman, H., et al. (2013) · Immunity · doi:10.1016/j.immuni.2012.10.020 · Cited by 1,338 · see citing works
Metabolic 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 · see citing works
T cell metabolism drives immunity
Buck, M. D., O’Sullivan, D., & Pearce, E. L. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20151159 · Cited by 1,190 · see citing works
Brüning, J. C., Michael, M. D., Winnay, J. N., Hayashi, T., Hörsch, D., Accili, D., Goodyear, L. J., & Kahn, C. R. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80155-0 · Cited by 1,183 · see citing works
Kulkarni, R., Brüning, J. C., Winnay, J. N., Postic, C., Magnuson, M. A., & Kahn, C. R. (1999) · Cell · doi:10.1016/s0092-8674(00)80546-2 · Cited by 1,148 · see citing works
Macintyre, A. N., Gerriets, V. A., Nichols, A., Michalek, R. D., Rudolph, M. C., Deoliveira, D., Anderson, S. M., Abel, E. D., Chen, B. J., Hale, L. P., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.05.004 · Cited by 1,129 · see citing works
Delgoffe, G. M., Pollizzi, K. N., Waickman, A. T., Heikamp, E., Meyers, D. J., Horton, M. R., Xiao, B., Worley, P. F., & Powell, J. D. (2011) · Nature Immunology · doi:10.1038/ni.2005 · Cited by 1,111 · see citing works
c-Myc Is a Universal Amplifier of Expressed Genes in Lymphocytes and Embryonic Stem Cells
Nie, Z., Hu, G., Wei, G., Cui, K., Yamane, A., Resch, W., Wang, R., Green, D. R., Tessarollo, L., Casellas, R. C., et al. (2012) · Cell · doi:10.1016/j.cell.2012.08.033 · Cited by 1,075 · see citing works
Obesity as a Major Risk Factor for Cancer
Pergola, G. D., & Silvestris, F. (2013) · Journal of Obesity · doi:10.1155/2013/291546 · Cited by 964 · see citing works
Sinclair, L. V., Rolf, J., Emslie, E., Shi, Y.-B., Taylor, P. M., & Cantrell, D. A. (2013) · Nature Immunology · doi:10.1038/ni.2556 · Cited by 930 · see citing works
Nakaya, M., Xiao, Y., Zhou, X., Chang, J., Chang, M., Cheng, X., Blonska, M., Lin, X., & Sun, S. (2014) · Immunity · doi:10.1016/j.immuni.2014.04.007 · Cited by 870 · see citing works
Jacobs, S. R., Herman, C. E., MacIver, N. J., Wofford, J. A., Wieman, H. L., Hammen, J. J., & Rathmell, J. C. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.7.4476 · Cited by 853 · see citing works
Carr, E. L., Kelman, A., Wu, G. S., Gopaul, R., Senkevitch, E., Aghvanyan, A., Turay, A. M., & Frauwirth, K. A. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0903586 · Cited by 830 · see citing works
The Energy Sensor AMPK Regulates T Cell Metabolic Adaptation and Effector Responses In Vivo
Blagih, J., Coulombe, F., Vincent, E. E., Dupuy, F., Galicia-Vázquez, G., Yurchenko, E., Raissi, T. C., van der Windt, G. J. W., Viollet, B., Pearce, E. L., et al. (2015) · Immunity · doi:10.1016/j.immuni.2014.12.030 · Cited by 659 · see citing works
Rao, R. R., Li, Q., Odunsi, K., & Shrikant, P. A. (2010) · Immunity · doi:10.1016/j.immuni.2009.10.010 · Cited by 656 · see citing works
Obesity and the risk and outcome of infection
Huttunen, R., & Syrjänen, J. (2012) · International Journal of Obesity · doi:10.1038/ijo.2012.62 · Cited by 595 · see citing works
Wieman, H. L., Wofford, J. A., & Rathmell, J. C. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-07-0593 · Cited by 593 · see citing works
T cell transfer model of chronic colitis: concepts, considerations, and tricks of the trade
Ostanin, D. V., Bao, J. R., Koboziev, I., Gray, L. T., Robinson-Jackson, S. A., Kosloski-Davidson, M., Price, V. H., & Grisham, M. B. (2008) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.90462.2008 · Cited by 444 · see citing works
Bar, R. S., Görden, P., Roth, J., Kahn, C. R., & MEYTS, P. D. (1976) · Journal of Clinical Investigation · doi:10.1172/jci108565 · Cited by 413 · see citing works
Dror, E., Dalmas, É., Meier, D. T., Wueest, S., Thévenet, J., Thienel, C., Timper, K., Nordmann, T. M., Traub, S., Schulze, F., et al. (2017) · Nature Immunology · doi:10.1038/ni.3659 · Cited by 396 · see citing works
Smith, A. G., Sheridan, P. A., Harp, J. B., & Beck, M. A. (2007) · Journal of Nutrition · doi:10.1093/jn/137.5.1236 · Cited by 389 · see citing works
Glucose Availability Regulates IFN-γ Production and p70S6 Kinase Activation in CD8+ Effector T Cells
Cham, C. M., & Gajewski, T. F. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.8.4670 · Cited by 359 · see citing works
Glucose transporter expression on the plasma membrane of resting and activated white blood cells
Maratou, E., Dimitriadis, G., Κόλλιας, Α., Boutati, E. I., Lambadiari, V., Mitrou, P., & Raptis, S. (2007) · European Journal of Clinical Investigation · doi:10.1111/j.1365-2362.2007.01786.x · Cited by 251 · see citing works
The cytotoxic T cell proteome and its shaping by the kinase mTOR
Hukelmann, J. L., Anderson, K. E., Sinclair, L. V., Grzes, K. M., Murillo, A. B., Hawkins, P. T., Stephens, L. R., Lamond, A. I., & Cantrell, D. A. (2016) · Nature Immunology · doi:10.1038/ni.3314 · Cited by 249 · see citing works
Viardot, A., Grey, S. T., Mackay, F., & Chisholm, D. J. (2006) · Endocrinology · doi:10.1210/en.2006-0686 · Cited by 173 · see citing works
Preston, G., Sinclair, L. V., Kaskar, A., Hukelmann, J. L., Navarro, M. N., Ferrero, I., MacDonald, H. R., Cowling, V. H., & Cantrell, D. A. (2015) · The EMBO Journal · doi:10.15252/embj.201490252 · Cited by 169 · see citing works
Insulin Inhibits IL-10–Mediated Regulatory T Cell Function: Implications for Obesity
Han, J. M., Patterson, S. J., Speck, M., Ehses, J. A., & Levings, M. K. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1302181 · Cited by 156 · see citing works
Milner, J. J., Rebeles, J., Dhungana, S., Stewart, D. A., Sumner, S., Meyers, M. H., Mancuso, P., & Beck, M. A. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1402295 · Cited by 137 · see citing works
Zhang, D. J., Wang, Q., Wei, J., Baimukanova, G., Buchholz, F., Stewart, A. F., Mao, X., & Killeen, N. P. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.11.6725 · Cited by 132 · see citing works
The Insulin Receptor Plays a Critical Role in T Cell Function and Adaptive Immunity
Fischer, H. J., Sie, C., Schumann, E., Witte, A., Dressel, R., van den Brandt, J., & Reichardt, H. M. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1601011 · Cited by 109 · see citing works
Translational control of c-MYC by rapamycin promotes terminal myeloid differentiation.
Wall, M., Poortinga, G., Hannan, K., Pearson, R., Hannan, R., & McArthur, G. (2008) · Blood · doi:10.1182/blood-2007-09-111856 · Cited by 103 · see citing works
Obesity Outweighs Protection Conferred by Adjuvanted Influenza Vaccination
Karlsson, E. A., Hertz, T., Johnson, C. N., Mehle, A., Krammer, F., & Schultz‐Cherry, S. (2016) · mBio · doi:10.1128/mbio.01144-16 · Cited by 95 · see citing works
Multiple Redundant Effector Mechanisms of CD8+ T Cells Protect against Influenza Infection
Hamada, H., Bassity, E., Flies, A., Strutt, T. M., García-Hernández, M. D. L. L., McKinstry, K. K., Zou, T., Swain, S. L., & Dutton, R. W. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1200571 · Cited by 94 · see citing works
Emergence of insulin receptors upon alloimmune T cells in the rat.
Helderman, J. H., & Strom, T. B. (1977) · Journal of Clinical Investigation · doi:10.1172/jci108646 · Cited by 91 · see citing works
Are Obesity-Related Insulin Resistance and Type 2 Diabetes Autoimmune Diseases?
Tsai, S., Clemente-Casares, X., Revelo, X. S., Winer, S., & Winer, D. (2015) · Diabetes · doi:10.2337/db14-1488 · Cited by 90 · see citing works
Self-citationMilner, J. J., Sheridan, P. A., Karlsson, E. A., Schultz‐Cherry, S., Shi, Q., & Beck, M. A. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1202429 · Cited by 78 · see citing works
Obesity is associated with activated and insulin resistant immune cells
Viardot, A., Heilbronn, L. K., Samocha‐Bonet, D., Mackay, F., Campbell, L. V., & Samaras, K. (2012) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.2302 · Cited by 77 · see citing works
Stentz, F. B., & Kitabchi, A. E. (2007) · Genomics Proteomics & Bioinformatics · doi:10.1016/s1672-0229(08)60009-1 · Cited by 76 · see citing works
Zhou, A. C., Wagar, L. E., Wortzman, M. E., & Watts, T. H. (2017) · Mucosal Immunology · doi:10.1038/mi.2016.124 · Cited by 67 · see citing works
Self-citationADAMTS5 Is a Critical Regulator of Virus-Specific T Cell Immunity
McMahon, M., Ye, S., Izzard, L., Dlugolenski, D. A., Tripp, R. A., Bean, A. G. D., McCulloch, D. R., & Stambas, J. (2016) · PLoS Biology · doi:10.1371/journal.pbio.1002580 · Cited by 58 · see citing works
Obesity-related immunodeficiency in patients with pandemic influenza H1N1
Nave, H., Beutel, G., & Kielstein, J. T. (2010) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(10)70304-2 · Cited by 51 · see citing works
De novo emergence of growth factor receptors in activated human CD4+ and CD8+ T lymphocytes
Stentz, F. B., & Kitabchi, A. E. (2003) · Metabolism · doi:10.1016/j.metabol.2003.07.015 · Cited by 34 · see citing works
Cukalac, T., Chadderton, J., Zeng, W., Cullen, J. G., Kan, W., Doherty, P. C., Jackson, D. C., Turner, S. J., & Gruta, N. L. L. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1301403 · Cited by 33 · see citing works
Milner, J. J., Wang, J., Sheridan, P. A., Ebbels, T. M. D., Beck, M. A., & Saric, J. (2014) · PLoS ONE · doi:10.1371/journal.pone.0097238 · Cited by 29 · see citing works
System A amino acid transporters regulate glutamine uptake and attenuate antibody‐mediated arthritis
Raposo, B., Vaartjes, D., Ahlqvist, E., Nandakumar, K. S., & Holmdahl, R. (2015) · Immunology · doi:10.1111/imm.12531 · Cited by 19 · see citing works
McInerney, M. F., Flynn, J. C., Goldblatt, P. J., Najjar, S. M., Sherwin, R. S., & Janeway, C. A. (1996) · The Journal of Immunology · doi:10.4049/jimmunol.157.8.3716 · Cited by 17 · see citing works
Insulin effect on glucose transport in thymocytes and splenocytes from rats with metabolic syndrome
Carbó, R., & Guarner‐Lans, V. (2010) · Diabetology & Metabolic Syndrome · doi:10.1186/1758-5996-2-64 · Cited by 14 · see citing works
Insulin binding to human cultured lymphocytes measured by flow cytometry using three ligands
Ziegler, O., Cantin, C., Germain, L., Dupuis, M., Sékaly, R., Drouin, P., & Chiasson, J. L. (1994) · Cytometry · doi:10.1002/cyto.990160408 · Cited by 6 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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 · see citing works
CD8+ T cell metabolism in infection and cancer
Reina-Campos, M., Scharping, N. E., & Goldrath, A. W. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00537-8 · Cited by 574 · see citing works
A Global View of the Interplay between Non-Alcoholic Fatty Liver Disease and Diabetes
Stefan, N., & Cusi, K. (2022) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(22)00003-1 · Cited by 593 · see citing works
Chronic inflammation and the hallmarks of aging
Baechle, J. J., Chen, N., Makhijani, P., Winer, S., Furman, D., & Winer, D. A. (2023) · Molecular Metabolism · doi:10.1016/j.molmet.2023.101755 · Cited by 471 · see citing works
Self-citationCoronavirus infections and type 2 diabetes-shared pathways with therapeutic implications
Drucker, D. J. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnaa011 · Cited by 399 · see citing works
SARS-CoV-2, COVID-19 and the aging immune system
Bartleson, J. M., Radenkovic, D., Covarrubias, A. J., Furman, D., Winer, D. A., & Verdin, E. (2021) · Nature Aging · doi:10.1038/s43587-021-00114-7 · Cited by 359 · see citing works
Self-citationHyperinsulinemia in Obesity, Inflammation, and Cancer
Zhang, A. M. Y., Wellberg, E. A., Kopp, J. L., & Johnson, J. D. (2021) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2020.0250 · Cited by 320 · see citing works
Metabolic adaptation of lymphocytes in immunity and disease
Chapman, N. M., & Chi, H.-B. (2022) · Immunity · doi:10.1016/j.immuni.2021.12.012 · Cited by 263 · see citing works
Cho, J.-W., Hong, M. H., Ha, S., Kim, Y., Cho, B. C., Lee, I., & Kim, H. R. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00493-8 · Cited by 267 · see citing works
Mechanical stiffness controls dendritic cell metabolism and function
Chakraborty, M., Chu, K., Shrestha, A., Revelo, X. S., Zhang, X., Gold, M. J., Khan, S., Lee, M., Huang, C., Akbari, M., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108609 · Cited by 258 · see citing works
Self-citationSignaling networks in immunometabolism
Saravia, J., Raynor, J. L., Chapman, N. M., Lim, S., & Chi, H.-B. (2020) · Cell Research · doi:10.1038/s41422-020-0301-1 · Cited by 217 · see citing works
Cellular metabolism regulates the differentiation and function of T-cell subsets
Ma, S., Ming, Y., Wu, J., & Cui, G. (2024) · Cellular and Molecular Immunology · doi:10.1038/s41423-024-01148-8 · Cited by 255 · see citing works
Targeting memory T cell metabolism to improve immunity
Corrado, M., & Pearce, E. L. (2022) · Journal of Clinical Investigation · doi:10.1172/jci148546 · Cited by 234 · see citing works
Gut-associated IgA+ immune cells regulate obesity-related insulin resistance
Luck, H., Khan, S. M., Kim, J. H., Copeland, J. K., Revelo, X. S., Tsai, S. J., Chakraborty, M., Cheng, K., Chan, Y. T., Nøhr, M. K., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11370-y · Cited by 204 · see citing works
Self-citationObesity and COVID-19: what makes obese host so vulnerable?
Mohammad, S., Aziz, R., Mahri, S. A., Malik, S. S., Haji, E. M., Khan, A. H., Khatlani, T., & Bouchama, A. (2021) · Immunity & Ageing · doi:10.1186/s12979-020-00212-x · Cited by 180 · see citing works
Emerging mechanisms of obesity-associated immune dysfunction
Shaikh, S. R., Beck, M. A., Alwarawrah, Y., & MacIver, N. J. (2023) · Nature Reviews Endocrinology · doi:10.1038/s41574-023-00932-2 · Cited by 173 · see citing works
Interaction of SHP‐2 SH2 domains with PD‐1 ITSM induces PD‐1 dimerization and SHP‐2 activation
Patsoukis, N., Duke-Cohan, J. S., Chaudhri, A., Aksoylar, H.-I., Wang, Q., Council, A., Berg, A., Freeman, G. J., & Boussiotis, V. A. (2020) · Communications Biology · doi:10.1038/s42003-020-0845-0 · Cited by 169 · see citing works
Targeting Mitochondrial-Derived Reactive Oxygen Species in T Cell-Mediated Autoimmune Diseases
Chávez, M. D., & Tse, H. M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.703972 · Cited by 169 · see citing works
Emerging concepts in intestinal immune control of obesity-related metabolic disease
Khan, S. M., Luck, H., Winer, S., & Winer, D. A. (2021) · Nature Communications · doi:10.1038/s41467-021-22727-7 · Cited by 150 · see citing works
Self-citationCalvo, S. S.-C., Bharath, L. P., Pugh, G. H., SantaCruz-Calvo, L., Lenin, R. R., Lutshumba, J., Liu, R., Bachstetter, A. D., Zhu, B., & Nikolajczyk, B. S. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00575-1 · Cited by 141 · see citing works
Necroptosis: A Novel Pathway in Neuroinflammation
Yu, Z., Jiang, N., Su, W., & Zhuo, Y. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.701564 · Cited by 133 · see citing works
The Immune Landscape of Visceral Adipose Tissue During Obesity and Aging
Khan, S. M., Chan, Y. T., Revelo, X. S., & Winer, D. A. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00267 · Cited by 126 · see citing works
Self-citationObesity as a Risk Factor for Severe COVID-19 and Complications: A Review
Demeulemeester, F., de Punder, K., van Heijningen, M., & van Doesburg, F. (2021) · Cells · doi:10.3390/cells10040933 · Cited by 122 · see citing works
Effects of dietary restriction on neuroinflammation in neurodegenerative diseases
Fontana, L., Ghezzi, L., Cross, A. H., & Piccio, L. M. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20190086 · Cited by 116 · see citing works
Insulin signaling establishes a developmental trajectory of adipose regulatory T cells
Li, Y., Lu, Y., Lin, S., Li, N., Han, Y., Huang, Q., Zhao, Y., Xie, F., Guo, Y., Deng, B., et al. (2021) · Nature Immunology · doi:10.1038/s41590-021-01010-3 · Cited by 99 · see citing works
The Emerging Role of YAP/TAZ in Tumor Immunity
Pan, Z., Tian, Y., Cao, C., & Niu, G. (2019) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-19-0375 · Cited by 95 · see citing works
Insulin as an immunomodulatory hormone
van Niekerk, G., Christowitz, C., Conradie, D., & Engelbrecht, A. (2019) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2019.11.006 · Cited by 93 · see citing works
The impact of obesity on immune response to infection: Plausible mechanisms and outcomes
Muscogiuri, G., Pugliese, G., Laudisio, D., Castellucci, B., Barrea, L., Savastano, S., & Colao, A. (2021) · Obesity Reviews · doi:10.1111/obr.13216 · Cited by 94 · see citing works
Specific Biological Features of Adipose Tissue, and Their Impact on HIV Persistence
Bourgeois, C., Gorwood, J., Barrail‐Tran, A., Lagathu, C., Capeau, J., Desjardins, D., Grand, R. L., Damouche, A., Béréziat, V., & Lambotte, O. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.02837 · Cited by 89 · see citing works
T Cell Immunosenescence in Aging, Obesity, and Cardiovascular Disease
Shirakawa, K., & Sano, M. (2021) · Cells · doi:10.3390/cells10092435 · Cited by 87 · see citing works
Multifactorial Basis and Therapeutic Strategies in Metabolism-Related Diseases
Guerra, J. V. D. S., Dias, M. M. G., Brilhante, A. J. V. C., Terra, M. F., García‐Arévalo, M., & Figueira, A. C. M. (2021) · Nutrients · doi:10.3390/nu13082830 · Cited by 87 · see citing works
The Activation Mechanism of the Insulin Receptor: A Structural Perspective
Choi, E., & Bai, X. (2023) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-052521-033250 · Cited by 82 · see citing works
Type 2 diabetes and viral infection; cause and effect of disease
Wensveen, T. T., Gašparini, D., Rahelić, D., & Wensveen, F. M. (2021) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2020.108637 · Cited by 80 · see citing works
Insulin and cancer: a tangled web
Leitner, B. P., Siebel, S., Akingbesote, N. D., Zhang, X., & Perry, R. J. (2022) · Biochemical Journal · doi:10.1042/bcj20210134 · Cited by 76 · see citing works
Regulation of the immune system by the insulin receptor in health and disease
Makhijani, P., Basso, P. J., Chan, Y. T., Chen, N., Baechle, J. J., Khan, S. M., Furman, D., Tsai, S. J., & Winer, D. A. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1128622 · Cited by 77 · see citing works
Self-citationDalamaga, Μ., Christodoulatos, G. S., Karampela, Ι., Vallianou, N. G., & Apovian, C. M. (2021) · Current Obesity Reports · doi:10.1007/s13679-021-00436-y · Cited by 74 · see citing works
Functional conservation in genes and pathways linking ageing and immunity
Fabian, D. K., Fuentealba, M., Dönertaş, H. M., Partridge, L., & Thornton, J. M. (2021) · Immunity & Ageing · doi:10.1186/s12979-021-00232-1 · Cited by 72 · see citing works
Metabolic disorders, COVID-19 and vaccine-breakthrough infections
Stefan, N. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00608-9 · Cited by 71 · see citing works
Regulatory T cells as metabolic sensors
de Candia, P., Procaccini, C., Russo, C., Lepore, M. T., & Matarese, G. (2022) · Immunity · doi:10.1016/j.immuni.2022.10.006 · Cited by 70 · see citing works
The effects of age and systemic metabolism on anti-tumor T cell responses
Drijvers, J. M., Sharpe, A. H., & Haigis, M. C. (2020) · eLife · doi:10.7554/elife.62420 · Cited by 69 · see citing works
Lin, Y., Luck, H., Khan, S. M., Schneeberger, P. H. H., Tsai, S. J., Clemente‐Casares, X., Lei, H., Leu, Y., Chan, Y. T., Chen, H., et al. (2019) · International Journal of Obesity · doi:10.1038/s41366-019-0340-1 · Cited by 67 · see citing works
Self-citationSadgrove, N. J., & Jones, G. L. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.02470 · Cited by 71 · see citing works
Varghese, E., Samuel, S. M., Líšková, A., Kubatka, P., & Büsselberg, D. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1009634 · Cited by 64 · see citing works
Hyperglycemia and Not Hyperinsulinemia Mediates Diabetes-Induced Memory CD8 T-Cell Dysfunction
Kavazović, I., Krapić, M., Beumer‐Chuwonpad, A., Polić, B., Wensveen, T. T., Lemmermann, N. A. W., van Gisbergen, K. P. J. M., & Wensveen, F. M. (2022) · Diabetes · doi:10.2337/db21-0209 · Cited by 63 · see citing works
Talamantes, S., Lisjak, M., Gilglioni, E. H., Llamoza-Torres, C. J., Ramos‐Molina, B., & Gurzov, E. N. (2023) · JHEP Reports · doi:10.1016/j.jhepr.2023.100811 · Cited by 60 · see citing works
Mitochondrial-encoded MOTS-c prevents pancreatic islet destruction in autoimmune diabetes
Kong, B. S., Min, S. H., Lee, C. D., & Cho, Y. M. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109447 · Cited by 62 · see citing works
Immunometabolism at the Heart of Cardiovascular Disease
DeBerge, M., Chaudhary, R. K., Schroth, S. L., & Thorp, E. B. (2023) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2022.12.010 · Cited by 57 · see citing works
Diabetes Status and Association With Risk of Tuberculosis Among Korean Adults
Yoo, J. E., Kim, D., Han, K., Rhee, S. Y., Shin, D. W., & Lee, H. J. (2021) · JAMA Network Open · doi:10.1001/jamanetworkopen.2021.26099 · Cited by 55 · see citing works
Metabolic regulation of T cells in the tumor microenvironment by nutrient availability and diet
Zhao, S., Peralta, R. M., Avina-Ochoa, N., Delgoffe, G. M., & Kaech, S. M. (2021) · Seminars in Immunology · doi:10.1016/j.smim.2021.101485 · Cited by 57 · see citing works
Control of T Cell Metabolism by Cytokines and Hormones
Bishop, E. L., Gudgeon, N. H., & Dimeloe, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.653605 · Cited by 53 · see citing works
Psyllium Fiber Protects Against Colitis Via Activation of Bile Acid Sensor Farnesoid X Receptor
Bretin, A., Zou, J., Yeoh, B. S., Ngo, V. L., Winer, S., Winer, D. A., Reddivari, L., Pellizzon, M., Walters, W. A., Patterson, A. D., et al. (2023) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2023.02.007 · Cited by 49 · see citing works
Self-citationImmunometabolism in the Tumor Microenvironment
Roy, D. G., Kaymak, I., Williams, K. S., Ma, E. H., & Jones, R. G. (2020) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030518-055817 · Cited by 48 · see citing works
PDIA3 epitope-driven immune autoreactivity contributes to hepatic damage in type 2 diabetes
Clement, C. C., Osan, J. K., Buqué, A., Nanaware, P. P., Chang, Y., Perino, G., Shetty, M., Yamazaki, T., Tsai, W. L., Urbanska, A. M., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abl3795 · Cited by 48 · see citing works
The fellowship of regulatory and tissue-resident memory cells
Barros, L., Ferreira, C., & Veldhoen, M. (2021) · Mucosal Immunology · doi:10.1038/s41385-021-00456-w · Cited by 41 · see citing works
Obesity-Mediated Immune Modulation: One Step Forward, (Th)2 Steps Back
Schmidt, V., Hogan, A. E., Fallon, P. G., & Schwartz, C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.932893 · Cited by 45 · see citing works
Mechanisms of gut microbiota-immune-host interaction on glucose regulation in type 2 diabetes
Zhou, Y.-D., Liang, F.-X., Tian, H.-R., Luo, D., Wang, Y., & Yang, S. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1121695 · Cited by 45 · see citing works
Macrophage Rewiring by Nutrient Associated PI3K Dependent Pathways
Sharif, O., Brunner, J. S., Vogel, A., & Schabbauer, G. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02002 · Cited by 44 · see citing works
The regulatory role of insulin in energy metabolism and leukocyte functions
Cruz-Pineda, W. D., Parra‐Rojas, I., Rodríguez-Ruiz, H. A., Illades‐Aguiar, B., Matia‐García, I., & Garibay‐Cerdenares, O. L. (2021) · Journal of Leukocyte Biology · doi:10.1002/jlb.2ru1220-847r · Cited by 44 · see citing works
Nageswaran, V., Carreras, A., Reinshagen, L., Beck, K. R., Steinfeldt, J., Henricsson, M., Rad, P. R., Peters, L., Strässler, E. T., Lim, J. J., et al. (2025) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.124.322346 · Cited by 48 · see citing works
T reg–specific insulin receptor deletion prevents diet-induced and age-associated metabolic syndrome
Wu, D., Wong, C. K., Han, J. M., Orban, P. C., Huang, Q. B., Gillies, J. K., Mojibian, M., Gibson, W. T., & Levings, M. K. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20191542 · Cited by 43 · see citing works
Watanabe, M., Balena, A., Masi, D., Tozzi, R., Risi, R., Caputi, A., Rossetti, R., Spoltore, M. E., Biagi, F., Anastasi, E., et al. (2022) · Vaccines · doi:10.3390/vaccines10010079 · Cited by 42 · see citing works
Gray, V., Chen, W., Tan, R. J. Y., Teo, J. M. N., Huang, Z., Fong, C. H.-Y., Law, T. W. H., Ye, Z., Yuan, S., Bao, X., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.10.004 · Cited by 41 · see citing works
Wensveen, F. M., Šestan, M., Wensveen, T. T., & Polić, B. (2019) · European Journal of Immunology · doi:10.1002/eji.201847895 · Cited by 41 · see citing works
Zheng, Y., Gou, X., Zhang, L., Gao, H., Wei, Y., Yu, X., Pang, B., Tian, J., Tong, X., & Li, M. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00360 · Cited by 43 · see citing works
Ratter-Rieck, J. M., Maalmi, H., Trenkamp, S., Zaharia, O., Rathmann, W., Schloot, N. C., Straßburger, K., Szendroedi, J., Herder, C., & Roden, M. (2021) · Diabetes · doi:10.2337/db21-0364 · Cited by 41 · see citing works
Spaceflight induces changes in gene expression profiles linked to insulin and estrogen
Mathyk, B. A., Tabetah, M., Karim, R. S., Zaksas, V., Kim, J., I, A. R., Muratani, M., Tasoula, A., Singh, R. S., Chen, Y.-K., et al. (2024) · Communications Biology · doi:10.1038/s42003-023-05213-2 · Cited by 40 · see citing works
Immunological Mechanisms of Sickness Behavior in Viral Infection
Krapić, M., Kavazović, I., & Wensveen, F. M. (2021) · Viruses · doi:10.3390/v13112245 · Cited by 41 · see citing works
Antidiabetic Properties of Plant Secondary Metabolites
Сухих, С. А., Babich, O., Prosekov, A. Y., Kalashnikova, O. B., Носкова, С., Bakhtiyarova, A., Krol, O., Tsvetkova, E. V., & Ivanova, S. A. (2023) · Metabolites · doi:10.3390/metabo13040513 · Cited by 39 · see citing works
Magnesium: The overlooked electrolyte in blood cancers?
Gile, J. J., Ruan, G. J., Abeykoon, J. P., McMahon, M. M., & Witzig, T. E. (2020) · Blood Reviews · doi:10.1016/j.blre.2020.100676 · Cited by 39 · see citing works
Starosz, A., Jamiołkowska‐Sztabkowska, M., Głowińska‐Olszewska, B., Moniuszko, M., Bossowski, A. T., & Grubczak, K. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.958430 · Cited by 38 · see citing works
Novel Molecular Evidence Related to COVID-19 in Patients with Diabetes Mellitus
Liao, Y., Zheng, J., Zheng, C., Lu, K., & Chao, Y. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9123962 · Cited by 36 · see citing works
Perspectives of Antidiabetic Drugs in Diabetes With Coronavirus Infections
Sun, B., Huang, S., & Zhou, J. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.592439 · Cited by 36 · see citing works
Muskiet, F. A. J., Carrera‐Bastos, P., Pruimboom, L., Lucía, A., & Furman, D. (2022) · Nutrients · doi:10.3390/nu14071388 · Cited by 34 · see citing works
He, Z., Khatib, A., & Creemers, J. W. M. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.05.001 · Cited by 33 · see citing works
Tibães, J. R. B., Silva, M. I. B., Wollin, B., Vine, D. F., Tsai, S. J., & Richard, C. (2023) · Obesity Reviews · doi:10.1111/obr.13665 · Cited by 32 · see citing works
Self-citationMorgante, G., Troìa, L., & Leo, V. D. (2020) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2020.105770 · Cited by 32 · see citing works
The immunology of sickness metabolism
Wensveen, F. M., Šestan, M., & Polić, B. (2024) · Cellular and Molecular Immunology · doi:10.1038/s41423-024-01192-4 · Cited by 34 · see citing works
Can Blood-Circulating Factors Unveil and Delay Your Biological Aging?
Rybtsova, N., Berezina, T. N., Kagansky, A., & Александрович, Р. С. (2020) · Biomedicines · doi:10.3390/biomedicines8120615 · Cited by 33 · see citing works
Shinjyo, N., & Kita, K. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.765217 · Cited by 29 · see citing works
Zhang, A. M. Y., Chu, K., Daly, B. F., Ruiter, T. J. J., Dou, Y., Yang, J. C. C., de Winter, T. J. J., Chhuor, J., Wang, S., Flibotte, S., et al. (2022) · Cancer & Metabolism · doi:10.1186/s40170-022-00282-z · Cited by 32 · see citing works
Pharmacological inhibition of GLUT1 as a new immunotherapeutic approach after myocardial infarction
Chen, Z., Dudek, J., Maack, C., & Hofmann, U. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114597 · Cited by 30 · see citing works
Colostrogenesis: Role and Mechanism of the Bovine Fc Receptor of the Neonate (FcRn)
Baumrucker, C. R., Macrina, A. L., & Bruckmaier, R. M. (2021) · Journal of Mammary Gland Biology and Neoplasia · doi:10.1007/s10911-021-09506-2 · Cited by 31 · see citing works
Breznik, J. A., Naidoo, A., Foley, K. P., Schulz, C., Lau, T. C., Loukov, D., Sloboda, D. M., Bowdish, D. M. E., & Schertzer, J. D. (2018) · Physiological Reports · doi:10.14814/phy2.13937 · Cited by 30 · see citing works
Ockenden, E. M., Russo, V. M., Leury, B. J., Giri, K., & Wales, W. J. (2023) · Animals · doi:10.3390/ani13050829 · Cited by 30 · see citing works
Host insulin resistance caused by Porphyromonas gingivalis-review of recent progresses
Jia, S., Li, X., & Du, Q. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1209381 · Cited by 28 · see citing works
Metabolic reprogramming of immune cells in MASH
Ma, C., Wang, S., Dong, B., & Tian, Y. (2025) · Hepatology · doi:10.1097/hep.0000000000001371 · Cited by 31 · see citing works
Gadaleta, E., Fourgoux, P., Pirro, S., Thorn, G. J., Nelan, R. L., Ironside, A. J., Rajeeve, V., Cutillas, P. R., Lobley, A., Wang, J., et al. (2020) · npj Breast Cancer · doi:10.1038/s41523-020-00182-9 · Cited by 27 · see citing works
Unmasking BACE1 in aging and age-related diseases
Bao, H., & Shen, Y. (2022) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2022.11.008 · Cited by 28 · see citing works
Shaikh, S. R., MacIver, N. J., & Beck, M. A. (2022) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-062320-115937 · Cited by 27 · see citing works
Lee, C., Gray, V., Teo, J. M. N., Tam, A. R., Fong, C. H.-Y., Lui, D. T. W., Pang, P., Chan, K. H., Hung, I. F., Tan, K. C. B., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1018393 · Cited by 26 · see citing works
Ratter, J. M., van Heck, J. I. P., Rooijackers, H. M. M., Jansen, H. J., van Poppel, P. C. M., Tack, C. J., & Stienstra, R. (2021) · Journal of Leukocyte Biology · doi:10.1002/jlb.3ab0120-019rr · Cited by 25 · see citing works
SARS-CoV-2 in diabetic pregnancies: a systematic scoping review
Eberle, C., James-Todd, T. M., & Stichling, S. (2021) · BMC Pregnancy and Childbirth · doi:10.1186/s12884-021-03975-3 · Cited by 25 · see citing works
Regulation of intestinal immunity by dietary fatty acids
Qiu, J., Ma, Y., & Qiu, J. (2022) · Mucosal Immunology · doi:10.1038/s41385-022-00547-2 · Cited by 27 · see citing works
Overweight and Obesity in Saudi Arabia: Consequences and Solutions
Alluhidan, M., Alsukait, R. F., Alghaith, T., Shekar, M., Alazemi, N., & Herbst, C. H. (2022) · World Bank, Washington, DC eBooks · doi:10.1596/978-1-4648-1828-8 · Cited by 26 · see citing works
Astroimmunology: the effects of spaceflight and its associated stressors on the immune system
Winer, D. A., Du, H., Kim, J., Chang, V., Burke, M., Winer, S., Costes, S. V., Frippiat, J., Sams, C. F., Paul, A. M., et al. (2025) · Nature reviews. Immunology · doi:10.1038/s41577-025-01226-6 · Cited by 26 · see citing works
Self-citationInsulin-mediated immune dysfunction in the development of preeclampsia
van Niekerk, G., Christowitz, C., & Engelbrecht, A. (2021) · Journal of Molecular Medicine · doi:10.1007/s00109-021-02068-0 · Cited by 24 · see citing works
Nutrition and immunity: perspectives on key issues and next steps
Dunbar, C. L., Aukema, H. M., Calder, P. C., Gibson, D. L., Henrickson, S. E., Khan, S., Mailhot, G., Panahi, S., Tabung, F. K., Tom, M., et al. (2023) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2022-0276 · Cited by 24 · see citing works
Self-citationKiernan, K., Alwarawrah, Y., Nichols, A., Danzaki, K., & MacIver, N. J. (2024) · Scientific Reports · doi:10.1038/s41598-024-54836-w · Cited by 24 · see citing works
Metformin enhances protection in guinea pigs chronically infected with Mycobacterium tuberculosis
Haugen, J. D., Ackart, D. F., Todd, A., DiLisio, J. E., Hoffman, S., Tanner, S., Kiran, D., Murray, M. B., Chicco, A. J., Obregón‐Henao, A., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-73212-y · Cited by 24 · see citing works
Host-Microbe-Pathogen Interactions: A Review of Vibrio cholerae Pathogenesis in Drosophila
Davoodi, S., & Foley, E. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2019.03128 · Cited by 23 · see citing works
- Authors
- Tsai, S., Clemente-Casares, X., Zhou, A. C., Lei, H., Ahn, J. J., Chan, Y. T., Choi, O., Luck, H., Woo, M., Dunn, S. E., Engleman, E. G., Watts, T. H., Winer, S., & Winer, D. A.
- Affiliations
- University Health Network (CA)
- University of Toronto (CA)
- Stanford University (US)
- St. Michael's Hospital (CA)
- Corresponding author
- Tsai, Sue
- Winer, Daniel A.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 28
- Issue
- 6
- Pages
- 922-934.e4
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2888838300
- Cited by
- 272
- References
- 53
- Citations by year
- 2026: 18 · 2025: 31 · 2024: 32 · 2023: 38 · 2022: 46 · 2021: 54 · 2020: 37 · 2019: 14 · 2018: 1
- FWCI
- 11.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (119414, 142708, 136884, 143250)
- FDN (148385)
- Canadian Diabetes Association (OG-3-15-5014, CS-5-12-3886)
- Bickell Foundation
- Banting and Best Diabetes Center Feasibility Operating
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- insulin receptor, T cell metabolism, immunometabolism, T cell immunity, colonic inflammation, influenza, glycolysis, mitochondrial respiration, nutrient uptake, inflammatory cytokines, T cell proliferation, insulin signaling
- MeSH terms
- Animals, Glycolysis, Humans, Immunity, Cellular, Inflammation, Influenza, Human, Insulin, Lymph Nodes, Lymphocyte Activation, Mice, Inbred C57BL, Orthomyxoviridae Infections, Receptor, Insulin, Spleen, T-Lymphocytes, Signal Transduction, Antigens, CD, T-Lymphocyte Subsets, Cytokines, Mice, Influenza A Virus, H1N1 Subtype
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review