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+CXCR3lo T-betlo cells (R1), CD28+CXCR3hiT-betint cells (R2), CD28–CXCR3intT-bethi cells (R3). The percentage of R3 in 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–CXCR3intT-bethi 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–CXCR3intT-bethi cells from SLE patients showed pronounced IFN-γ production compared to HCs (T-bethi 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–CXCR3intT-bethi 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–CXCR3intT-bethi cells 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–CXCR3intT-bethi cells and their metabolic reprogramming as a potential target for pathological process in SLE.
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 October 28, 2020.
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