Metabolic Control of Invariant Natural Killer T Cell Function

Kevin Wei¹, Deepak A. Rao², Pui Y. Lee³, Anqi Gao⁴, Peter A. Nigrovic⁵ and Michael Brenner⁶, ¹Rheumatology, Immunology & Allergy, Brigham & Women's Hospital, Boston, MA, ²Internal Medicine/Rheumatology, Brigham & Womens Hospital, Boston, MA, ³Division of Immunology, Boston Children's Hospital, Boston, MA, ⁴Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA, ⁵Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, ⁶Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: T cells and metabolism

Session Information

Date: Sunday, November 8, 2015

Title: T cell Biology and Targets in Autoimmune Disease I

Session Type: ACR Concurrent Abstract Session

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

Background/Purpose:

Invariant Natural Killer T (iNKT) cells are a unique subset of T cells that shape an inflammatory response through rapid production of large amounts of cytokines following activation. Perturbation in frequency and proliferative response of peripheral blood iNKT cells have been described in rheumatoid arthritis and systemic lupus erythematosus, however the mechanism is not well understood. Metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis is crucial for T cell proliferation and cytokine production. The aim of this study is to characterize metabolic reprogramming during iNKT cell activation.

Methods:

Peripheral blood iNKT cell frequency from rheumatoid arthritis patients and healthy controls were measured by flow cytometry. Cultured mouse iNKT cells were used for metabolic analysis. iNKT cell oxygen consumption and extracellular acidification were measured using a Seahorse XFe24 analyzer. Specific pharmacologic inhibitors 2-deoxyglucose (glycolysis) and oligomycin (oxidative phosphorylation) tested specific metabolic pathways for iNKT cell function.

Results:

Compared with healthy controls, rheumatoid arthritis patients had a decreased frequency of peripheral blood iNKT cells. Metabolic analysis of murine iNKT cell revealed predominant reliance on oxidative phosphorylation at basal state. Upon stimulation with the cognate lipid antigen alpha-galactosylceramide, iNKT cells exhibit significantly enhanced glycolysis and glycolytic capacity. In contrast, oxidative phosphorylation was only modestly elevated while spare respiratory capacity was suppressed following activation. Glycolysis, but not oxidative phosphorylation, has been shown to be essential for interferon-gamma production in MHC-restricted T-cells. In contrast, inhibition of either glycolysis or oxidative phosphorylation in iNKT cells resulted in dose-dependent suppression of interferon-gamma production, suggesting differential metabolic control in iNKT cells

Conclusion:

In summary, peripheral blood iNKT cells are significantly reduced in rheumatoid arthritis patients. Our data suggest that metabolic reprogramming and glucose utilization play a crucial role in iNKT cell function. Further characterization of iNKT cell metabolic state in rheumatoid arthritis patients may shed light on mechanisms of altered iNKT cell function during chronic inflammation.

Disclosure: K. Wei, None; D. A. Rao, None; P. Y. Lee, None; A. Gao, None; P. A. Nigrovic, None; M. Brenner, None.

To cite this abstract in AMA style:

Wei K, Rao DA, Lee PY, Gao A, Nigrovic PA, Brenner M. Metabolic Control of Invariant Natural Killer T Cell Function [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/metabolic-control-of-invariant-natural-killer-t-cell-function/. Accessed .

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