Reduced Mitochondrial Respiration in Peripheral T Cells After Paediatric Heamatopoietic Stem Cell Transplantation

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2024 Jan 25

PMID 38268913

Authors

Kasper Molgaard

Katrine Kielsen

Marianne Ifversen

Ozcan Met

Inge Marie Svane

Klaus Muller

Affiliations

Soon will be listed here.

Abstract

Background: Recovery and functional differentiation of T-cell subsets are central for the development of immune function and complications after allogeneic hematopoietic stem cell transplantation (HSCT), but little is known about the cellular respiration and factors influencing T-cell metabolic fitness during immune maturation after HSCT.

Method: We included 20 HSCT patients and analysed mitochondrial oxidative phosphorylation and mitochondrial fitness in peripheral blood mononuclear cell samples collected at days +90 and +180 after HSCT.

Results: Phenotypic analysis revealed lower overall T-cell counts, lower CD4+/CD8+ ratio and a skewed distribution of early T-cell subsets at day +90, gradually recovering by day +180. Although ATP turnover in HSCT patients was similar to healthy controls, the spare respiratory capacity (SRC) of T cells, reflecting the available energy reserve, was significantly reduced at day +90 and +180 compared to healthy controls. This reduction in SRC was not correlated with the occurrence of acute graft-versus-host disease (aGVHD), the intensity of conditioning regimens and markers of T-cell exhaustion.

Conclusion: We found significantly depressed SRC until six months post-HSCT, but we were not able to identify transplant-related risk factors or associations with the clinical outcome.

References

van der Windt G, Everts B, Chang C, Curtis J, Freitas T, Amiel E . Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2011; 36(1):68-78. PMC: 3269311. DOI: 10.1016/j.immuni.2011.12.007. View

Ahmadzadeh M, Johnson L, Heemskerk B, Wunderlich J, Dudley M, White D . Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009; 114(8):1537-44. PMC: 2927090. DOI: 10.1182/blood-2008-12-195792. View

Cieri N, Camisa B, Cocchiarella F, Forcato M, Oliveira G, Provasi E . IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood. 2012; 121(4):573-84. DOI: 10.1182/blood-2012-05-431718. View

Teague R, Sather B, Sacks J, Huang M, Dossett M, Morimoto J . Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Nat Med. 2006; 12(3):335-41. DOI: 10.1038/nm1359. View

Pearce E, Poffenberger M, Chang C, Jones R . Fueling immunity: insights into metabolism and lymphocyte function. Science. 2013; 342(6155):1242454. PMC: 4486656. DOI: 10.1126/science.1242454. View

Kielsen K, Jordan K, Uhlving H, Pontoppidan P, Shamim Z, Ifversen M . T cell reconstitution in allogeneic haematopoietic stem cell transplantation: prognostic significance of plasma interleukin-7. Scand J Immunol. 2014; 81(1):72-80. DOI: 10.1111/sji.12244. View

Pearce E, Walsh M, Cejas P, Harms G, Shen H, Wang L . Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature. 2009; 460(7251):103-7. PMC: 2803086. DOI: 10.1038/nature08097. View

Sukumar M, Liu J, Ji Y, Subramanian M, Crompton J, Yu Z . Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J Clin Invest. 2013; 123(10):4479-88. PMC: 3784544. DOI: 10.1172/JCI69589. View

Kielsen K, Ryder L, Lennox-Hvenekilde D, Gad M, Nielsen C, Heilmann C . Reconstitution of Th17, Tc17 and Treg cells after paediatric haematopoietic stem cell transplantation: Impact of interleukin-7. Immunobiology. 2017; 223(2):220-226. DOI: 10.1016/j.imbio.2017.10.023. View

10.

Ferrara J, Levine J, Reddy P, Holler E . Graft-versus-host disease. Lancet. 2009; 373(9674):1550-61. PMC: 2735047. DOI: 10.1016/S0140-6736(09)60237-3. View

11.

Storek J, Gooley T, Witherspoon R, Sullivan K, Storb R . Infectious morbidity in long-term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts. Am J Hematol. 1997; 54(2):131-8. DOI: 10.1002/(sici)1096-8652(199702)54:2<131::aid-ajh6>3.0.co;2-y. View

12.

Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell L . PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015; 6:6692. PMC: 4389235. DOI: 10.1038/ncomms7692. View

13.

Cascone T, McKenzie J, Mbofung R, Punt S, Wang Z, Xu C . Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy. Cell Metab. 2018; 27(5):977-987.e4. PMC: 5932208. DOI: 10.1016/j.cmet.2018.02.024. View

14.

Ogonek J, Juric M, Ghimire S, Varanasi P, Holler E, Greinix H . Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol. 2016; 7:507. PMC: 5112259. DOI: 10.3389/fimmu.2016.00507. View

15.

Sukumar M, Kishton R, Restifo N . Metabolic reprograming of anti-tumor immunity. Curr Opin Immunol. 2017; 46:14-22. PMC: 6327315. DOI: 10.1016/j.coi.2017.03.011. View

16.

Roux E, van Lier R, Hale G, Helg C, Chapuis B, Starobinski M . Reconstitution of the T-cell compartment after bone marrow transplantation: restoration of the repertoire by thymic emigrants. Blood. 1998; 92(11):4464-71. View

17.

Couriel D, Saliba R, Giralt S, Khouri I, Andersson B, de Lima M . Acute and chronic graft-versus-host disease after ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant. 2004; 10(3):178-85. DOI: 10.1016/j.bbmt.2003.10.006. View

18.

Rangel Rivera G, Knochelmann H, Dwyer C, Smith A, Wyatt M, Rivera-Reyes A . Fundamentals of T Cell Metabolism and Strategies to Enhance Cancer Immunotherapy. Front Immunol. 2021; 12:645242. PMC: 8014042. DOI: 10.3389/fimmu.2021.645242. View

19.

Molgaard K, Rahbech A, Met O, Marie Svane I, Straten P, Desler C . Real-time Monitoring of Mitochondrial Respiration in Cytokine-differentiated Human Primary T Cells. J Vis Exp. 2021; (176). DOI: 10.3791/62984. View

20.

Peeters M, Aehnlich P, Pizzella A, Molgaard K, Seremet T, Met O . Mitochondrial-Linked Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules. Front Immunol. 2021; 12:718863. PMC: 8652221. DOI: 10.3389/fimmu.2021.718863. View