Background. Naïve and memory CD8 T cells have been shown to exhibit different metabolic profiles, especially upon antigen stimulation. However, it is unknown whether the prolonged stimulation of the immune system in allogeneic transplantation modifies the metabolic profiles of CD8 T cell subsets. In this report, we aimed to characterize at the usage of ATP upon antigen-stimulation and to identify the source of ATP in CD8 lymphocytes in healthy volunteers and in kidney transplant recipients.

Method. ATP level of CD8 subsets (naïve; effector memory, EM; TEMRA) from healthy volunteers (HV) and patients with stable kidney graft (TX) was quantified before and after polyclonal stimulation (PMA & Iono or aCD3 +/- IL-2 or IL-15). Mitochondria polarization was assessed using MitoTracker Red and JC-1. CD25 and CD69 expression was monitored after 2 days of culture with the aforementioned stimuli in the presence of inhibitor of glycolysis (2-DG) or glutaminolysis (DON).

Results. Antigen-experienced CD8 (EM and TEMRA) exhibit a greater ATP reservoir as compared to naïve CD8 in HV whereas CD8 from TX patients exhibit similar level of ATP across the different subsets. Of interest, antigen-experienced CD8 from TX are able to reconstitute more efficiently their ATP pool as compared to those of HV upon polyclonal stimulation. Antigen-experienced CD8 from TX exhibit a greater amount of well-polarized mitochondria as compared to those of HV. Finally, we report that CD8 TEMRA preferentially use glutamine-based metabolism whereas CD8 EM preferentially use glycolysis. Indeed, stimulation with anti-CD3 and IL-2 or IL-15 induced the early upregulation of CD69 that is inhibited by the provision of 2-DG for EM and not in TEMRA CD8.

Conclusion. Kidney transplantation results in the differentiation of antigen-experienced CD8 T cells with a metabolic machinery fitted to sustain strong stimulation. Moreover, pathogenic TEMRA CD8 T cells exhibit a strong accumulation of ATP with a differential usage of nutriment as compared to EM CD8 T cells. Metabolic interferences can efficiently control pathogenic CD8 T cells from TX but need to be adjusted according to the immune challenge.

CITATION INFORMATION: Tilly G, Yap M, Giral M, Brouard S, Pecqueur C, Degauque N. Kidney Allotransplantation Induces the Differentiation of Antigen-Experienced CD8 T Cells with Enhanced Metabolic Profiles. Am J Transplant. 2016;16 (suppl 3).

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