Skip to main content
SpringerLink
Log in

Assessment of the Mitochondrial Condition in CD4+ and CD8+ T-Lymphocytes from Healthy Subjects

  • Published:
Cell and Tissue Biology Aims and scope Submit manuscript

Abstract

Despite the active study of T-lymphocyte mitochondria under pathology, data on the organelles’ condition in healthy people are not presented in the available literature. The aim of this work was to assess mitochondrial condition in CD4+ and CD8+ T-lymphocytes of healthy subjects. In both cell subsets, the mitochondrial mass and mitochondrial membrane potential, as well as the content of the mitochondrial-activity regulator (PGC-1α), were determined by flow cytometry. Naive and memory cells, as well as resting and cycling lymphocytes were compared. It was shown for the first time that in healthy subjects, mitochondrial condition differs between CD4+ and CD8+ T-lymphocytes. Despite the cell maturation stage or resting/cycling status, the mass and membrane potential of mitochondria in CD4+ T-lymphocytes significantly exceed those in CD8+ T-cells. Both CD4+ and CD8+ T-lymphocytes have higher mitochondrial mass, mitochondrial membrane potential, and PGC-1α content in memory cells and cycling elements. Furthermore in healthy individuals, the relationship between the level of the mitochondrial activity regulator and the indices of mitochondrial condition differ significantly between CD4+ and CD8+ T-lymphocytes: in CD4+ T-cells, the PGC-1α content is directly related to the mass of mitochondria, but in CD8+ T-lymphocytes, it is directly related with the organelles’ transmembrane potential.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.

Similar content being viewed by others

REFERENCES

  1. Ahrends, T., Spanjaard, A., Pilzecker, B., Babala, N., Bovens, A., Xiao, Y., Jacobs, H. and Borst, J., CD4(+) T cell help confers a cytotoxic T cell effector program including coinhibitory receptor downregulation and increased tissue invasiveness, Immunity, 2017, vol. 47, p. 848.

    Article  CAS  Google Scholar 

  2. Bengsch, B., Johnson, A.L., Kurachi, M., Odorizzi, P.M., Pauken, K.E., Attanasio, J., Stelekati, E., McLane, L.M., Paley, M.A., Delgoffe, G.M., and Wherry, E.J., Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8(+) T cell exhaustion, Immunity, 2016, vol. 45, p. 358.

    Article  CAS  Google Scholar 

  3. Callender, L.A., Carroll, E.C., Bober, E.A., Akbar, A.N., Solito, E., and Henson, S.M., Mitochondrial mass governs the extent of human T cell senescence, Aging Cell, 2020, vol. 19, article ID e13067.

    Article  CAS  Google Scholar 

  4. Cheng, C.F., Ku, H.C., and Lin, H., PGC-1alpha as a pivotal factor in lipid and metabolic regulation, Int. J. Mol. Sci., 2018, vol. 19, p. 3447.

    Article  Google Scholar 

  5. Cottet-Rousselle, C., Ronot, X., Leverve, X., and Mayol., J.F., Cytometric assessment of mitochondria using fluorescent probes, Cytometry A, 2011, vol. 79, p. 405.

    Article  Google Scholar 

  6. Farber, D.L., Yudanin, N.A., and Restifo, N.P., Human memory T cells: generation, compartmentalization and homeostasis, Nat. Rev. Immunol., 2014, vol. 14, p. 24.

    Article  CAS  Google Scholar 

  7. Fernandez-Marcos, P.J. and Auwerx, J., Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis, Am. J. Clin. Nutr., 2011, vol. 93, p. 884S.

    Article  CAS  Google Scholar 

  8. Jones, N., Cronin, J.G., Dolton, G., Panetti, S., Schauenburg, A.J., Galloway, S.A.E., Sewell, A.K., Cole, D.K., Thornton, C.A., and Francis, N.J., Metabolic adaptation of human CD4+ and CD8+ T-cells to T-cell receptor-mediated stimulation, Front. Immunol., 2017, vol. 8, p. 1516.

    Article  Google Scholar 

  9. Kaech, S.M. and Wherry, E.J., Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection, Immunity, 2007, vol. 27, p. 393.

    Article  CAS  Google Scholar 

  10. MacIver, N.J., Michalek, R.D., and Rathmell, J.C., Metabolic regulation of T lymphocytes, Annu. Rev. Immunol., 2013, vol. 31, p. 259.

    Article  CAS  Google Scholar 

  11. McKinney, E.F. and Smith, K.G.C., Metabolic exhaustion in infection, cancer and autoimmunity, Nat. Immunol., 2018, vol. 19, p. 213.

    Article  CAS  Google Scholar 

  12. McLane, L.M., Abdel-Hakeem, M.S., and Wherry, E.J., CD8 T cell exhaustion during chronic viral infection and cancer, Annu. Rev. Immunol., 2019, vol. 37, p. 457.

    Article  CAS  Google Scholar 

  13. Mumprecht, S., Schurch, C., Schwaller, J., Solentha-ler, M., and Ochsenbein, A.F., Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression, Blood, 2009, vol. 114, p. 1528.

    Article  CAS  Google Scholar 

  14. Nicoli, F., Papagno, L., Frere, J.J., Cabral-Piccin, M.P., Clave, E., Gostick, E., Toubert, A., Price, D.A., Caputo, A., and Appay, V., Naive CD8(+) T-cells engage a versatile metabolic program upon activation in humans and differ energetically from memory CD8(+) T-cells, Front. Immunol., 2018, vol. 9, p. 2736.

    Article  CAS  Google Scholar 

  15. Novy, P., Quigley, M., Huang, X., and Yang, Y., CD4 T cells are required for CD8 T cell survival during both primary and memory recall responses, J. Immunol., 2007, vol. 179, p. 8243.

    Article  CAS  Google Scholar 

  16. Phan, A.T., Doedens, A.L., Palazon, A., Tyrakis, P.A., Cheung, K.P., Johnson, R.S. and Goldrath, A.W., Constitutive glycolytic metabolism supports CD8(+) T cell effector memory differentiation during viral infection, Immunity, 2016, vol. 45, p. 1024.

    Article  CAS  Google Scholar 

  17. Ponnappan, S. and Ponnappan, U., Aging and immune function: molecular mechanisms to interventions, Antioxid. Redox. Signal., 2011, vol. 14, p. 1551.

    Article  CAS  Google Scholar 

  18. Presley, A.D., Fuller, K.M., and Arriaga, E.A., MitoTracker Green labeling of mitochondrial proteins and their subsequent analysis by capillary electrophoresis with laser-induced fluorescence detection, J. Chromatogr. B Anal. Technol. Biomed. Life Sci., 2003, vol. 793, p. 141.

    Article  CAS  Google Scholar 

  19. Rogers, P.R., Dubey, C., and Swain, S.L., Qualitative changes accompany memory T cell generation: faster, more effective responses at lower doses of antigen, J. Immunol., 2000, vol. 164, p. 2338.

    Article  CAS  Google Scholar 

  20. Saeidi, A., Zandi, K., Cheok, Y.Y., Saeidi, H., Wong, W.F., Lee, C.Y.Q., Cheong, H.C., Yong, Y.K., Larsson, M., and Shankar, E.M., T-cell exhaustion in chronic infections: Reversing the state of exhaustion and reinvigorating optimal protective immune responses, Front. Immunol., 2018, vol. 9, p. 2569.

    Article  Google Scholar 

  21. Sallusto, F., Lenig, D., Forster, R., Lipp, M., and Lanzavecchia, A., Two subsets of memory T lymphocytes with distinct homing potentials and effector functions, Nature, 1999, vol. 401, p. 708.

    Article  CAS  Google Scholar 

  22. Spinelli, J.B. and Haigis, M.C., The multifaceted contributions of mitochondria to cellular metabolism, Nat. Cell Bi-l., 2018, vol. 20, p. 745.

    Article  CAS  Google Scholar 

  23. Sukumar, M., Liu, J., Mehta, G.U., Patel, S.J., Roychoudhuri, R., Crompton, J.G., Klebanoff, C.A., Ji, Y., Li, P., Yu, Z., Whitehill, G.D., Clever, D., Eil, R.L., Palmer, D.C., Mitra, S., Rao, M., et al., Mitochondrial membrane potential identifies cells with enhanced stemness for cellular therapy, Cell Metab., 2016, vol. 23, p. 63.

    Article  CAS  Google Scholar 

  24. Sun, H. and Li, X., Metabolic reprogramming in resting and activated immune cells, Metabolomics (Los Angel), 2017, vol. 7, p. 188.

    CAS  PubMed  Google Scholar 

  25. Toma, G., Lemnian, I.M., Karapetian, E., Grosse, I., and Seliger, B., Transcriptional analysis of total CD8(+) T cells and CD8(+)CD45RA(-) memory T cells from young and old healthy blood donors, Front. Immunol., 2022, vol. 13, p. 806906. https://doi.org/10.3389/fimmu.2022.806906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Van der Windt, G.J., Everts, B., Chang, C.H., Curtis, J.D., Freitas, T.C., Amiel, E., Pearce, E.J., and Pearce, E.L., Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development, Immunity, 2012, vol. 36, p. 68.

    Article  CAS  Google Scholar 

  27. Van der Windt, G.J., O’Sullivan, D., Everts, B., Huang, S.C., Buck, M.D., Curtis, J.D., Chang, C.H., Smith, A.M., Ai, T., Faubert, B., Jones, R.G., Pearce, E.J., and Pearce, E.L., CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability, Proc. Natl. Acad. Sci. U. S. A., 2013, vol. 110, p. 14336.

    Article  CAS  Google Scholar 

  28. Yang, P., Ma, J., Yang, X., and Li, W., Peripheral CD4+ naive/memory ratio is an independent predictor of survival in non-small cell lung cancer, Oncotarget, 2017, vol. 8, p. 83650.

    Article  Google Scholar 

  29. Younes, S.A., Talla, A., Pereira Ribeiro, S., Saidakova, E.V., Korolevskaya, L. B., Shmagel, K. V., Shive, C. L., Freeman, M. L., Panigrahi, S., Zweig, S., Balderas, R., Margolis, L., Douek, D. C., Anthony, D. D., Pandiyan, P., et al., Cycling CD4+ T cells in HIV-infected immune nonresponders have mitochondrial dysfunction, J. Clin. Invest., 2018, vol. 128, p. 5083.

    Article  Google Scholar 

  30. Yu, F., Hao, Y., Zhao, H., Xiao, J., Han, N., Zhang, Y., Dai, G., Chong, X., Zeng, H. and Zhang, F., Distinct mitochondrial disturbance in CD4+T and CD8+T cells from HIV-infected patients, J. Acquired Immune Defic. Syndr., 2017, vol. 74, p. 206.

    Article  CAS  Google Scholar 

  31. Yu, Y.R., Imrichova, H., Wang, H., Chao, T., Xiao, Z., Gao, M., Rincon-Restrepo, M., Franco, F., Genolet, R., Cheng, W.C., Jandus, C., Coukos, G., Jiang, Y.F., Locasale, J.W., Zippelius, A., Liu, P.S., et al., Disturbed mitochondrial dynamics in CD8(+) TILs reinforce T cell exhaustion, Nat. Immunol., 2020, vol. 21, p. 1540.

    Article  CAS  Google Scholar 

  32. Zhu, J., Yamane, H., and Paul, W.E., Differentiation of effector CD4 T cell populations (*), Annu. Rev. Immunol., 2010, vol. 28, p. 445.

    Article  CAS  Google Scholar 

Download references

Funding

The work was performed as part of the state order “The Role of CD4+ Memory T-cell Metabolism in Disrupted Immunity Regeneration in HIV-Infected Patients Undergoing Antiretroviral Therapy,” state reg. no. 121112500044-9.

Author information

Authors and Affiliations

  1. Institute of Ecology and Genetics of Microorganisms, Ural Branch, Russian Academy of Sciences, Perm Federal Research Center, Ural Branch, Russian Academy of Sciences, 614081, Perm, Russia

    L. B. Korolevskaya, E. V. Saidakova, N. G. Shmagel & K. V. Shmagel

Authors
  1. L. B. Korolevskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. V. Saidakova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. G. Shmagel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K. V. Shmagel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L. B. Korolevskaya.

Ethics declarations

Conflict of interest. The authors declare that they have no conflicts of interest.

Statement of compliance with standards of research involving humans as subjects. All studies involving people were carried out in accordance with the principles of institutional and/or national committees on biomedical ethics and the Declaration of Helsinki of 1964 and its subsequent emendations or comparable ethical principles. Each participant provided voluntary informed consent. The work was approved by the Local Bioethics Committee of the Perm Regional Center for Prevention and Control of AIDS and Infectious Diseases, reg. no. IRB00008964.

Additional information

Translated by A. Deryabina

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Korolevskaya, L.B., Saidakova, E.V., Shmagel, N.G. et al. Assessment of the Mitochondrial Condition in CD4+ and CD8+ T-Lymphocytes from Healthy Subjects. Cell Tiss. Biol. 16, 470–477 (2022). https://doi.org/10.1134/S1990519X22050054

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1990519X22050054

Keywords:

Search

Navigation