Skip to main content

T lymphocyte depletion ameliorates age-related metabolic impairments in mice

GeroScience volume 43, pages 1331–1347 (2021)Cite this article

Abstract

Both glucose tolerance and adaptive immune function exhibit significant age-related alterations. The influence of the immune system on obesity-associated glucose intolerance is well characterized; however, whether the immune system contributes to age-related glucose intolerance is not as well understood. Here, we report that advancing age results in an increase in T cell infiltration in the epididymal white adipose tissue (eWAT), liver, and skeletal muscle. Subtype analyses show that both CD4+, CD8+ T cells are greater with advancing age in each of these tissues and that aging results in a blunted CD4 to CD8 ratio. Anti-CD3 F(ab’)2 fragments depleted CD4+ and CD8+ cells in eWAT, CD4+ cells only in the liver, and did not deplete quadriceps T cells. In old mice, T cells producing both interferon-γ and tumor necrosis factor-α are accumulated in the eWAT and liver, and a greater proportion of skeletal muscle T cells produced interferon-γ. Aging resulted in increased proportion and numbers of T regulatory cells in eWAT, but not in the liver or muscle. Aging also resulted in greater numbers of eWAT and quadriceps CD206- macrophages and eWAT, liver and quadriceps B cells; neither cell type was altered by anti-CD3 treatment. Anti-CD3 treatment improved glucose tolerance in old mice and was accompanied by improved signaling related to liver and skeletal muscle insulin utilization and decreased gluconeogenesis-related gene expression in the liver. Our findings indicate a critical role of the adaptive immune system in the age-related metabolic dysfunction.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

References

  1. Brewer RA, Gibbs VK, Smith DL Jr. Targeting glucose metabolism for healthy aging. Nutrition and Healthy Aging. 2016;4(1):31–46. https://doi.org/10.3233/NHA-160007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Chia CW, Egan JM, Ferrucci L. Age-related changes in glucose metabolism, hyperglycemia, and cardiovascular risk. Circ Res. 2018;123(7):886–904. https://doi.org/10.1161/CIRCRESAHA.118.312806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Czech MP. Insulin action and resistance in obesity and type 2 diabetes. Nat Med. 2017;23(7):804–14. https://doi.org/10.1038/nm.4350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rines AK, Sharabi K, Tavares CD, Puigserver P. Targeting hepatic glucose metabolism in the treatment of type 2 diabetes. Nat Rev Drug Discov. 2016;15(11):786–804. https://doi.org/10.1038/nrd.2016.151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, et al. Endotext. 2000.

  6. Palmer AK, Kirkland JL. Aging and adipose tissue: potential interventions for diabetes and regenerative medicine. Exp Gerontol. 2016;86:97–105. https://doi.org/10.1016/j.exger.2016.02.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Frasca D, Blomberg BB, Paganelli R. Aging, obesity, and inflammatory age-related diseases. Front Immunol. 2017;8:1745. https://doi.org/10.3389/fimmu.2017.01745.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med. 2009;15(8):914–20. https://doi.org/10.1038/nm.1964.

    Article  CAS  PubMed  Google Scholar 

  9. Donath MY. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov. 2014;13(6):465–76. https://doi.org/10.1038/nrd4275.

    Article  CAS  PubMed  Google Scholar 

  10. Lesniewski LA, Hosch SE, Neels JG, de Luca C, Pashmforoush M, Lumeng CN, et al. Bone marrow-specific Cap gene deletion protects against high-fat diet-induced insulin resistance. Nat Med. 2007;13(4):455–62. https://doi.org/10.1038/nm1550.

    Article  CAS  PubMed  Google Scholar 

  11. Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 2012;18(3):363–74. https://doi.org/10.1038/nm.2627.

    Article  CAS  PubMed  Google Scholar 

  12. Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J, et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med. 2009;15(8):921–9. https://doi.org/10.1038/nm.2001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stout MB, Justice JN, Nicklas BJ, Kirkland JL. Physiological aging: Links among adipose tissue dysfunction, diabetes, and frailty. Physiology (Bethesda, Md). 2017;32(1):9–19. https://doi.org/10.1152/physiol.00012.2016.

    Article  CAS  Google Scholar 

  14. Bapat SP, Myoung Suh J, Fang S, Liu S, Zhang Y, Cheng A, et al. Depletion of fat-resident Treg cells prevents age-associated insulin resistance. Nature. 2015;528(7580):137–41. https://doi.org/10.1038/nature16151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wu D, Wong CK, Han JM, Orban PC, Huang Q, Gillies J, et al. T reg-specific insulin receptor deletion prevents diet-induced and age-associated metabolic syndrome. J Exp Med. 2020;217(8). doi: 10.1084/jem.20191542.

  16. McLaughlin T, Liu LF, Lamendola C, Shen L, Morton J, Rivas H, et al. T-cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans. Arterioscler Thromb Vasc Biol. 2014;34(12):2637–43. https://doi.org/10.1161/ATVBAHA.114.304636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Medrikova D, Sijmonsma TP, Sowodniok K, Richards DM, Delacher M, Sticht C, et al. Brown adipose tissue harbors a distinct sub-population of regulatory T cells. PLoS One. 2015;10(2):e0118534. https://doi.org/10.1371/journal.pone.0118534.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ghazarian M, Revelo XS, Nøhr MK, Luck H, Zeng K, Lei H, et al. Type I interferon responses drive intrahepatic T cells to promote metabolic syndrome. Sci Immunol. 2017;2(10). doi: 10.1126/sciimmunol.aai7616.

  19. Šestan M, Marinović S, Kavazović I, Cekinović Đ, Wueest S, Turk Wensveen T, et al. Virus-induced interferon-γ causes insulin resistance in skeletal muscle and derails glycemic control in obesity. Immunity. 2018;49(1):164-77.e6. doi: 10.1016/j.immuni.2018.05.005.

  20. Hirsch R, Bluestone JA, DeNenno L, Gress RE. Anti-CD3 F(ab')2 fragments are immunosuppressive in vivo without evoking either the strong humoral response or morbidity associated with whole mAb. Transplantation. 1990;49(6):1117–23.

    Article  CAS  PubMed  Google Scholar 

  21. Zamarron BF, Mergian TA, Cho KW, Martinez-Santibanez G, Luan D, Singer K, et al. Macrophage proliferation sustains adipose tissue inflammation in formerly obese mice. Diabetes. 2017;66(2):392–406. https://doi.org/10.2337/db16-0500.

    Article  CAS  PubMed  Google Scholar 

  22. Donato AJ, Henson GD, Morgan RG, Enz RA, Walker AE, Lesniewski LA. TNF-alpha impairs endothelial function in adipose tissue resistance arteries of mice with diet-induced obesity. Am J Phys Heart Circ Phys. 2012;303(6):H672–9. https://doi.org/10.1152/ajpheart.00271.2012.

    Article  CAS  Google Scholar 

  23. Lumeng CN, Liu J, Geletka L, Delaney C, Delproposto J, Desai A, et al. Aging is associated with an increase in T cells and inflammatory macrophages in visceral adipose tissue. J Immunol. 2011;187(12):6208–16. https://doi.org/10.4049/jimmunol.1102188.

    Article  CAS  PubMed  Google Scholar 

  24. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest. 2006;116(6):1494–505. https://doi.org/10.1172/JCI26498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796–808. https://doi.org/10.1172/JCI19246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zamboni M, Armellini F, Harris T, Turcato E, Micciolo R, Bergamo-Andreis IA, et al. Effects of age on body fat distribution and cardiovascular risk factors in women. Am J Clin Nutr. 1997;66(1):111–5. https://doi.org/10.1093/ajcn/66.1.111.

    Article  CAS  PubMed  Google Scholar 

  27. Pascot A, Lemieux S, Lemieux I, Prud'homme D, Tremblay A, Bouchard C, et al. Age-related increase in visceral adipose tissue and body fat and the metabolic risk profile of premenopausal women. Diabetes Care. 1999;22(9):1471–8.

    Article  CAS  PubMed  Google Scholar 

  28. Callahan JE, Kappler JW, Marrack P. Unexpected expansions of CD8-bearing cells in old mice. J Immunol. 1993;151(12):6657–69.

    CAS  PubMed  Google Scholar 

  29. Trott DW, Henson GD, Ho MHT, Allison SA, Lesniewski LA, Donato AJ. Age-related arterial immune cell infiltration in mice is attenuated by caloric restriction or voluntary exercise. Exp Gerontol. 2018;109:99–107. https://doi.org/10.1016/j.exger.2016.12.016.

    Article  CAS  PubMed  Google Scholar 

  30. Singh P, Coskun ZZ, Goode C, Dean A, Thompson-Snipes L, Darlington G. Lymphoid neogenesis and immune infiltration in aged liver. Hepatology. 2008;47(5):1680–90. https://doi.org/10.1002/hep.22224.

    Article  PubMed  Google Scholar 

  31. Mehta P, Nuotio-Antar AM, Smith CW. γδ T cells promote inflammation and insulin resistance during high fat diet-induced obesity in mice. J Leukoc Biol. 2015;97(1):121–34. https://doi.org/10.1189/jlb.3A0414-211RR.

    Article  CAS  PubMed  Google Scholar 

  32. Shirakawa K, Yan X, Shinmura K, Endo J, Kataoka M, Katsumata Y, et al. Obesity accelerates T cell senescence in murine visceral adipose tissue. J Clin Invest. 2016;126:4626–39. https://doi.org/10.1172/JCI8860610.1172/JCI88606.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Deyhle MR, Hyldahl RD. The role of T lymphocytes in skeletal muscle repair from traumatic and contraction-induced injury. Front Physiol. 2018;9:768. https://doi.org/10.3389/fphys.2018.00768.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kuswanto W, Burzyn D, Panduro M, Wang KK, Jang YC, Wagers AJ, et al. Poor repair of skeletal muscle in aging mice reflects a defect in local, interleukin-33-dependent accumulation of regulatory T cells. Immunity. 2016;44(2):355–67. https://doi.org/10.1016/j.immuni.2016.01.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang Y, Wehling-Henricks M, Welc SS, Fisher AL, Zuo Q, Tidball JG. Aging of the immune system causes reductions in muscle stem cell populations, promotes their shift to a fibrogenic phenotype, and modulates sarcopenia. FASEB J. 2019;33(1):1415–27. https://doi.org/10.1096/fj.201800973R.

    Article  CAS  PubMed  Google Scholar 

  36. Kim IH, Xu J, Liu X, Koyama Y, Ma HY, Diggle K, et al. Aging increases the susceptibility of hepatic inflammation, liver fibrosis and aging in response to high-fat diet in mice. Age (Dordr). 2016;38(4):291–302. https://doi.org/10.1007/s11357-016-9938-6.

    Article  CAS  Google Scholar 

  37. Camell CD, Günther P, Lee A, Goldberg EL, Spadaro O, Youm YH, et al. Aging induces an Nlrp3 inflammasome-dependent expansion of adipose B cells that impairs metabolic homeostasis. Cell Metab. 2019;30(6):1024-39.e6. doi: 10.1016/j.cmet.2019.10.006.

  38. Stienstra R, van Diepen JA, Tack CJ, Zaki MH, van de Veerdonk FL, Perera D, et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc Natl Acad Sci U S A. 2011;108(37):15324–9. https://doi.org/10.1073/pnas.1100255108.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011;17(2):179–88. https://doi.org/10.1038/nm.2279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yang Q, Vijayakumar A, Kahn BB. Metabolites as regulators of insulin sensitivity and metabolism. Nat Rev Mol Cell Biol. 2018;19(10):654–72. https://doi.org/10.1038/s41580-018-0044-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hakimi P, Johnson MT, Yang J, Lepage DF, Conlon RA, Kalhan SC, et al. Phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolism. Nutr Metab (Lond). 2005;2:33. https://doi.org/10.1186/1743-7075-2-33.

    Article  CAS  Google Scholar 

  42. Heidemann C, Sun Q, van Dam RM, Meigs JB, Zhang C, Tworoger SS, et al. Total and high-molecular-weight adiponectin and resistin in relation to the risk for type 2 diabetes in women. Ann Intern Med. 2008;149(5):307–16. https://doi.org/10.7326/0003-4819-149-5-200809020-00005.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Ueno D, Masaki T, Gotoh K, Chiba S, Kakuma T, Yoshimatsu H. Cilnidipine regulates glucose metabolism and levels of high-molecular adiponectin in diet-induced obese mice. Hypertens Res. 2013;36(3):196–201. https://doi.org/10.1038/hr.2012.141.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the National Institutes of Health grants, K01 AG061271 (DWT), R01 AG060395 (AJD), and R01 AG048366 (LAL), and the Veteran’s Affairs Merit Review Award I01 BX004492 (LAL) from the US Department of Veterans Affairs Biomedical Laboratory Research and Development Service.

Author information

Author notes

  1. Daniel W. Trott and Md Torikul Islam contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA

    Daniel W. Trott, Anthony J. Donato, Tavia Dutson, Eric S. Sorensen, Jinjin Cai, Venkateswara R. Gogulamudi, Tam T. T. Phuong & Lisa A. Lesniewski

  2. Department of Kinesiology, University of Texas at Arlington, Arlington, TX, USA

    Daniel W. Trott & David J. Buckley

  3. Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA

    Md Torikul Islam, Anthony J. Donato & Lisa A. Lesniewski

  4. Geriatrics Research Education and Clinical Center, Veteran’s Affairs Medical Center, GRECC Bldg 2 Rm 2D08, 500 Foothill Drive, Salt Lake City, UT, 84148, USA

    Anthony J. Donato & Lisa A. Lesniewski

  5. Department of Biochemistry, University of Utah, Salt Lake City, UT, USA

    Anthony J. Donato

Authors
  1. Daniel W. Trott
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Md Torikul Islam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David J. Buckley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anthony J. Donato
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tavia Dutson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eric S. Sorensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jinjin Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Venkateswara R. Gogulamudi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tam T. T. Phuong
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lisa A. Lesniewski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lisa A. Lesniewski.

Ethics declarations

Disclosures

None.

Disclaimer

The contents do not represent the views of the U.S. Department of Veterans Affairs, the National Institutes of Health, or the US government.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(PDF 205 kb)

About this article

Verify currency and authenticity via CrossMark

Cite this article

Trott, D.W., Islam, M.T., Buckley, D.J. et al. T lymphocyte depletion ameliorates age-related metabolic impairments in mice. GeroScience 43, 1331–1347 (2021). https://doi.org/10.1007/s11357-021-00368-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-021-00368-4

Keywords

  • Adipose tissue
  • T lymphocyte
  • Macrophages
  • Glucose intolerance
  • Liver
  • Skeletal muscle