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Utilizing Changing Patterns of T-cell Metabolism in Aging for Effective Immunosuppression

Y. Nian, T. Heinbokel, K. Minami, R. Maenosono, J. Iske, A. El Khal, S. G. Tullius

Transplant Surgery Research Lab, Brigham and Women’s Hospital, Boston, MA

Meeting: 2019 American Transplant Congress

Abstract number: 266

Keywords: Graft survival, Immunosuppression, T cell activation, T helper cells

Session Information

Session Name: Concurrent Session: Immunosuppression Preclinical Studies

Session Type: Concurrent Session

Date: Monday, June 3, 2019

Session Time: 2:30pm-4:00pm

 Presentation Time: 3:42pm-3:54pm

Location: Room 309

*Purpose: Metabolic reprogramming has been identified as a critical regulator of immunity. Little is known on changes of T-cell metabolism in aging and how to utilize metabolic targets for immunosuppression. Here, we show that T-cell metabolism changes drastically in aging. Most notably, targeting T-cell metabolism provides an age-specific and effective immunosuppression.

*Methods: Naïve CD4+ T cells were collected from C57BL/6 mice (3 and 18 mths) and activated with anti-CD3 and anti-CD28 for 24 hrs. Oxidative phosphorylation (OXPHOS) and aerobic glycolysis were assessed by oxygen consumption (OCR) and extracellular acidification rate (ECAR) using a Seahorse XFe96 extracellular flux analyzer. Full thickness skin grafts were transplanted from young (3 mth DBA/2 mice) to young and old C57BL/6 recipients (3 and 18 mths). Immune profiling was performed at sequential time intervals using a FACS Canton II flow cytometer.

*Results: Old, but not young CD4+ T cells demonstrated compromised metabolic rates with significantly lower OCR and ECAR rates (p<0.0001). Moreover, old CD4+ T cells demonstrated a significant mitochondrial impairment with compromised respiratory and glycolytic capacities (p<0.0001). These results indicated a limited capacity of old CD4+ T cells to respond to metabolic stress. Glutaminolysis has been identified as a critical metabolic pathway in T-cell immunity. 6-diazo-5-oxo-l-norleucine (DON) is an analog of glutamine that inhibits critical enzymes of glutaminolysis. DON treatment inhibited IL-2 production in both young and old CD4+ T. To test the immunosuppressive capacity in fully mismatched transplantation model from DBA/2 donor to either young or old C57BL/6 recipients, recipients of full-thickness skin allografts were treated with DON (1.6mg/kg every other day/x60). Most impressive were age-specific differences: DON improved graft survival times in young animals from 7 to 18 days; in old recipients DON prolonged graft survival to 43 days (n=7, p<0.001)). Of note, treatment with DON had been superior to TAC treatment (in young recipients: TAC treated vs control vs DON = 7 vs 11 vs 18 days; in old recipients old TAC treated vs control vs DON=10 vs 14 vs 43 days, n=7, p<0.001). Immune profiling by day 7 showed a 41% reduction of CD4+ T cell proliferation in the old but not young recipients. (n=5, p<0.001). However, DON induced an age-specific increase of in IL-10 production (44% in old, no significant difference in young, n=5, p<0.001). Moreover, DON inhibited the frequency of CD4+IL-2+ T cells more robustly in old recipients (34% vs 13%, young vs old, n=5, p<0.001). DON appeared to specifically targeting CD-4+ T-cells as CD8+ T cells numbers and function were not impacted by DON treatment.

*Conclusions: Inhibiting glutaminolysis demonstrates an effective immunosuppression targeting old CD4+ T-cells. Those experimental data provide a novel concept of immunosuppression with relevance in older recipients.

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To cite this abstract in AMA style:

Nian Y, Heinbokel T, Minami K, Maenosono R, Iske J, Khal AEl, Tullius SG. Utilizing Changing Patterns of T-cell Metabolism in Aging for Effective Immunosuppression [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/utilizing-changing-patterns-of-t-cell-metabolism-in-aging-for-effective-immunosuppression/. Accessed June 6, 2025.

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