Metabolic Reprogramming in CD4+CD28-CXCR3intt-bethi cells and Its Relevance to Pathogenesis in Patients with SLE

Shigeru Iwata¹, Yuka Kanno², Kei Sakata^3,4, Maiko Hajime¹, Masataka Torigoe^1,5, Naoaki Ohkubo¹, Shingo Nakayamada⁶, John J O'Shea⁷ and Yoshiya Tanaka⁸, ¹The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan, ²National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, ³Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan, ⁴The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyshu, Japan, ⁵Department of Endocrinology, Metabolism, Rheumatology and Nephrology,, Faculty of Medicine, Oita University, Yufu, Oita, Japan, Yufu, Japan, ⁶First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan, ⁷NIAMS NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, ⁸University of Occupational and Environmental Health, Kitakyushu, Japan

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: SLE, T cells and metabolism

Session Information

Date: Monday, November 14, 2016

Title: Systemic Lupus Erythematosus – Human Etiology and Pathogenesis - Poster I

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: CD4⁺ T cells play a crucial role in pathological process of Systemic Lupus Erythematosus (SLE). Recently, importance of metabolic reprograming in immunocompetent cells was highlighted. We found that preferential induction of T-bet by IFN-γ is an important factor for shift to glycolysis in activated CD4⁺T cells in vitro. In this study, we examine the mechanism by which IFN-γ and T-bet in CD4⁺T cells involved in pathogenesis of SLE.

Methods: Peripheral blood mononuclear cells were obtained from 19 healthy controls (HCs), 30 patients with bio-naïve active RA and 60 patients with active SLE. The expression of CXCR3, T-bet, mTORC1 phosphorylation and IFN-γ production in CD4⁺T cells were measured by flow cytometry, and assessed the correlation with clinical characteristics.

Results: We found that CD4⁺ T cells consisted of 3 subsets of CD28⁺CXCR3^loT-bet^locells(R1), CD28⁺CXCR3^hiT-bet^int cells (R2), CD28^–CXCR3^intT-bet^hi cells (R3). The percentage of R3in SLE patients was significantly higher compared to HCs (HCs; 1.1±0.2%, RA; 5.5±1.8%, p=0.06, SLE; 5.6±1.1%, p=0.02). CD4⁺CD28^–CXCR3^intT-bet^hi cells mainly consisted of CD45RA^–CCR7^– effector memory cells and were significantly activated compared to other subsets (HLA-DR⁺CD38⁺ cells; R1: 2.8±0.6%, R2: 11.2±1.5%, R3: 27.6±2.3%, p<0.0001, ANOVA). CD4⁺CD28^–CXCR3^intT-bet^hicells from SLE patients showed pronounced IFN-γ production compared to HCs (T-bet^hi IFN-γ⁺ cells; HCs: 1.1±0.4%, RA: 1.7±0.6%, p=0.50, SLE: 5.6±1.3%, p=0.04). Interestingly, the ratio of CD4⁺CD28^–CXCR3^intT-bet^hi cells was significantly correlated with the number of immunosuppressants previously used for the SLE patients, that is treatment-resistant (p=0.03, logistic regression analysis). Phosphorylation of mTORC1, which is important for shift to glycolysis, in CD4⁺ T cells from patients with RA and SLE was significantly increased compared to HCs (ΔMFI of p-mTORC1; HCs: 284.9, RA: 563, p=0.01, SLE: 511.7, p=0.03). T-bet expression was significantly correlated with mTOC1 phosphorylation and IFN-γ production in CD4⁺T cells from patients with SLE (p-mTORC1: r=0.4718, p<0.01, IFN-γ production: r=0.4915, p=0.01, Pearson).

Conclusion: These results indicated that CD4⁺CD28^–CXCR3^intT-bet^hicells might be related to refractory to established therapies in patients with SLE. In addition, these cells are constitutively activated accompanied with shift to glycolysis through IFN-γ-mTORC1-T-bet pathway. We highlight CD4⁺CD28^–CXCR3^intT-bet^hi cells and their metabolic reprogramming as a potential target for pathological process in SLE.

Disclosure: S. Iwata, None; Y. Kanno, None; K. Sakata, N/A, 3; M. Hajime, None; M. Torigoe, None; N. Ohkubo, None; S. Nakayamada, None; J. J. O'Shea, None; Y. Tanaka, N/A, 5.

To cite this abstract in AMA style:

Iwata S, Kanno Y, Sakata K, Hajime M, Torigoe M, Ohkubo N, Nakayamada S, O'Shea JJ, Tanaka Y. Metabolic Reprogramming in CD4+CD28-CXCR3intt-bethi cells and Its Relevance to Pathogenesis in Patients with SLE [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/metabolic-reprogramming-in-cd4cd28-cxcr3intt-bethi-cells-and-its-relevance-to-pathogenesis-in-patients-with-sle/. Accessed .

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