Background: Energy metabolism of immune cells has been identified as critical in driving alloimmunity. While metabolic capacities change with aging, aspects linking age, immunosuppression, and T-cell metabolism remain unclear. We submit that age-specific immunosuppressive capacities of Tacrolimus (TAC) are operative through specific changes in T-cell metabolism.

Methods: Skin grafts were transplanted from young (DBA/2 mice) to young or old C57BL/6 recipients; animals were treated with TAC and graft survival was tested. Aging and TAC treatment, naïve CD4+ T cells were collected from recipient animals and activated with anti-CD3 and anti-CD28. Oxidative phosphorylation (OXPHOS) and aerobic glycolysis were assessed by oxygen consumption (OCR) and extracellular acidification rate (ECAR) using a XFe24 extracellular flux analyzer.

Results: Old and young recipients received weight-adapted doses of TAC. The majority of older recipients survived until the end of the observation period (day 30) while young animals rejected allografts by day 11(p < 0.0004). Old CD4+ T cells demonstrated compromised metabolic rates with lower OCR and ECAR (p<0.0001). Next, we co-cultured naïve CD4+ T cells with TAC at different concentrations and measured OCR and ECAR. Dose-response curves of ECAR to TAC revealed a reduced IC50 of old CD4+ T cells (p<0.0001). Next, we tested if metabolism in CD4+ T cells impacts IL-2 in an age-specific manner. Here, we used glyceraldehyde 3- phosphate (G3P) to induce glycolysis in-vitro. G3P is the sole substrate of GAPDH, the pivotal enzyme in glycolysis. Activation of glycolysis increased IL-2 in old treated CD4+ T cells. Moreover, IL-2 expression increased by 82% subsequent to the introduction of G3P in old TAC treated T cells; only a minor (26%) increase of G3P was observed in old naïve T cells suggesting a compromised glycolysis in old CD4+ T cells, an effect that is exacerbated by TAC.

Conclusions: TAC appears significantly effective in older recipients leading to age-specific prolongation of graft survival. Those effects are linked to age-specific metabolic changes in CD4+ T-cell metabolism with a compromised glycolysis of old CD4+ T cells that is exacerbated age-specifically subsequent to TAC treatment. Moreover, IL-2 expression increased in old CD4+ T cells following the activation of glycolysis. Taken together, our results suggest that age-specific aspects of TAC are linked to a compromised glycolysis of CD4+ T cells.

CITATION INFORMATION: Nian Y., Heinbokel T., Minami K., Abdi R., Elkhal A., Tullius S. Age-Specific Effects of Tacrolimus Are Associated to Specific Changes of T Cell Metabolism Am J Transplant. 2017;17 (suppl 3).

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