Tuesday September 15, 2020 - 23:30 to 00:15
Targeting CD4+ T cell metabolism provides an effective and age-specific immunosuppression
Yeqi Nian1, Timm Heinbokel1, Koichiro Minami1, Ryoichi Maenosono1, Jasper Iske1, Abdallah Elkhal1, Stefan G. Tullius1.
1Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
Targeting T-cell metabolism may provide an effective immunosuppression. We delineated the correlation of aging and T cell metabolism. Moreover, we defined the consequences of metabolic changes in T-cell compartments on alloimmunity and delineated specific and novel immunosuppressive targets on CD-4+ T-cells. We collected naïve CD4+ T cells (splenocytes) of young and old (3 and 18 months) C67BL/6 mice. Following activation with anti-CD3 and anti-CD28 (24 hrs), we evaluated oxidative phosphorylation (OXPHOS) and aerobic glycolysis by oxygen consumption (OCR) and extracellular acidification (ECAR) using a Seahorse XFe96 extracellular flux analyzer. Graft survival, T-cell specificity and a detailed immune profiling were recorded serially. Upon activation in-vitro, a compromised utilization of OXPHOS and glycolysis pathways was observed in old CD4+ T cells (p<0.0001), indicating failure of old CD4+ T cells to exhibit adequate metabolic reprogramming. Further analysis of metabolic pathways revealed a critical role of glutaminolysis in T cell activation. 6-diazo-5-oxo-l-norleucine (DON), an analog of glutamine inhibiting critical enzymes of glutaminolysis resulted into an age-specific reduced activation and proliferative capacities of CD4+T cells. Notably, lower doses of DON inhibited IL-2 production and CFSE-determined proliferation only in old but not young CD4+ T cells (p<0.001). Utilizing a pre-clinical fully mismatched transplantation model, we observed inversed CD4:CD8 ratio in old recipients following DON (1.6mg/kg every other day). Graft survival was prolonged in young recipients, from 7 to 18 days (p< 0.01). Notably, was a drastic and age-specific effect of DON on graft skin graft survival in old recipients to 42 days (n=7, p<0.001). Targeting metabolic pathways was specific to CD4+ T-cells. Adoptively transferring young CD4+ T cells reversed the prolonged survival observed in old recipients. Depletion of CD8+ T cells did not alter transplant outcomes of DON in either young or old recipients. Taken together, we introduce a detailed and age-specific analysis of metabolic pathways in T cells and introduce a novel concept for an optimized immunosuppression in old recipients.