Date: Sunday, November 8, 2015
Session Title: T cell Biology and Targets in Autoimmune Disease I
Session Type: ACR Concurrent Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: Rheumatoid arthritis (RA) is a T cell dependent disease in which chronically activated immune cells cause progressive damage of articular cartilage and bone. RA T cells adapt their metabolic programs to support their chronic energy needs in a disease-specific pattern. Unlike healthy T cells, RA T cells fail to upregulate glycolytic flux due to suppression of the glycolytic enzyme PFKFB3, produce low concentrations of lactate and ATP and are energy deprived. The energy status of cells is monitored by AMP-activated protein kinase (AMPK), a nutrient-sensing “master-regulator” that enforces quiescence under conditions of energy stress by restraining mTORC1 activity. Here, we have explored how energy deficiency affects signaling pathways in RA T cells and how it shapes their effector functions.
Methods: Purified naïve CD4 T cells from RA patients and age-matched controls were stimulated with anti-CD3/CD28. Transcripts of AMPK components and autophagy-related genes were measured by RT-PCR. AMPK activity was assessed by Western blot analysis of AMPK targets, including p-p70-S6K and pACC1. Autophagic flux was measured by immunoblotting for LC3 conversion. Treg cells were induced under polarizing conditions with TGF-β1 and IL-2. FoxP3+cells were quantified by flow cytometry 7 days after polarization.
Results: Compared to healthy CD4 T cells, RA T cells had reduced levels of p-AMPKα(Thr172) (p<0.05) indicating insufficient activation of the AMPK signaling axis. Protein subcomponents of AMPK, including AMPKα, β and γ were intact. Functional evidence for insufficient AMPK signaling in RA T cells came from the demonstration that mTORC1 activity was inappropriately high, captured by protein levels of p-p70-S6K (p<0.05) and pACC1 (p<0.05). Also, autophagy, an AMPK-dependent energy supply mechanism, was impaired in RA T cells (p<0.05).
To test whether AMPK was able to respond to stress signals, we deprived T cells of glucose by culturing them in the glucose analogue 2-DG. AMPK activation induced by energy stress was reduced in RA. To examine whether additional AMPK-dependent pathways were impaired, we examined the induction of anti-inflammatory Treg cells from naive RA T cells. Compared to healthy control T cells, RA T cells failed to differentiate into FoxP3+Tregs.
Conclusion: RA T cells are energy deprived and are unable to correct their energy status due to defective responsiveness of the nutrient sensor AMPK. Functional consequences of insufficient AMPK activation include the failure of autophagy, defective upregulation of glycolysis, insufficient inhibition of lipogenesis and, most importantly, chronic hyperactivity of the immune activator mTORC1.
To cite this abstract in AMA style:Yang Z, Matteson EL, Hong J, Goronzy J, Weyand CM. Failure in Nutrient Sensing Supports mTOR Hyperactivity and Proinflammatory Functions in T Cells from Patients with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/failure-in-nutrient-sensing-supports-mtor-hyperactivity-and-proinflammatory-functions-in-t-cells-from-patients-with-rheumatoid-arthritis/. Accessed October 27, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/failure-in-nutrient-sensing-supports-mtor-hyperactivity-and-proinflammatory-functions-in-t-cells-from-patients-with-rheumatoid-arthritis/