Rational. We have recently shown that the accumulation of TEMRA CD8 in kidney transplant recipients (Tx) is associated with a higher risk of kidney dysfunction. Nevertheless, factors leading to their accumulation and activation, particularly the role of cytokines, remain ill-defined and alternative therapeutics are needed to control their inflammatory response. Thus, we hypothesized that the effector functions of TEMRA CD8 are triggered by proinflammatory cytokine IL-15 and that drugs interfering with specific metabolic processes would constitute a valuable option to control their pathogenicity.

Method. TEMRA, NA[Iuml]VE and EM CD8 were purified from Tx with stable graft function at 1 year (n=56) and from healthy volunteers (HV). Survival, proliferation (Cell_Proliferation_Dye) and activation (CD25, CD69) were monitored upon stimulation with IL-15 +/- aCD3. Inflammation of HUVEC induced by soluble factors secreted by IL-15 stimulated TEMRA was monitored (upregulation of CX3CL1). Contribution of glycolysis, glutaminolysis and oxidative phosphorylation to TEMRA response was tested using 2-DG, DON and oligomycin respectively.

Results. We show that IL-15 combined with TCR stimulation induces the rapid activation of TEMRA CD8 from Tx patients (upregulation of CD25 and CD69) and fosters the activation of the endothelium (upregulation of CX3CL1 by HUVEC) in an IFN-g and TNF-a dependent manner. IL-15 induces anti-apoptotic signals and promotes vigorous proliferation dependent on PI3K/Akt, MAPK and ERK pathways. Resting TEMRA cells are metabolically more active than naive and EM, as shown by their high ATP reservoir and a high expression of genes involved in glycolysis, glutaminolysis and Pentose_Phosphate_Pathway. Upon stimulation, TEMRA adapt their metabolism by sustaining an increased mitochondrial respiration and glycolysis. Finally, we show that the inhibition of glycolysis and to a lesser extent of glutaminolysis is effective at preventing the endothelium inflammation induced by Tx TEMRA CD8.

Conclusion. Our findings demonstrate that IL-15 is a potent activator of TEMRA CD8 in Tx patients and that selective glycolytic and glutaminolytic inhibition blunts the TEMRA induced inflammation of the endothelium.

CITATION INFORMATION: Doan-Ngoc T.-M, Tilly G, Yap M, Caristan A, Jacquemont L, Danger R, Cadoux M, Bruneau S, Giral M, Guerif P, Nicol B, Garcia A, Laplaud D, Brouard S, Pecqueur C, Degauque N. Glycolytic and Glutaminolytic Metabolism Supports IL-15 Induced Inflammatory Response of Temra CD8 from Kidney Transplant Recipients. Am J Transplant. 2017;17 (suppl 3).

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