Upregulation of SLAMF3 on Human T cells Is Induced by Palmitic Acid Through the STAT5-PI3K/Akt Pathway and Features the Chronic Inflammatory Profiles of Type 2 Diabetes

Abstract

Background: Metabolic stress-induced low-grade chronic inflammation plays an important role in the development of insulin-resistance and type 2 diabetes (T2D). Emerging evidence highlights the importance of directly elucidating T cell activation under the obesity-induced metabolic stress condition and the underline mechanisms, which remain elusive. Methods: T cells from T2D patients and health controls were analyzed for activation and cytokine production by flow cytometry. The effect of palmitic acid on T cells was assessed by in vitro assays. RNA sequencing and inhibitor blocking assays were used to determine the signaling pathways involved in palmitic acid-induced SLAMF3 upregulation on T cells. Findings: We found a significant upregulation of SLAMF3, a molecule regulates immune function through homophilic interactions, on T cells from T2D patients compared to those of healthy controls. Importantly, SLAMF3 upregulation was associated with an increased ability to produce proinflammatory cytokines including IFN-γ and IL-17. Additionally, SLAMF3high T cells were significantly more sensitive than SLAMF3low T cells to TCR stimulation with anti-CD3/CD28 antibodies. Palmitic acid was found to cause significant upregulation of SLAMF3 on primary human T cells as well as Jurkat cells. Further mechanistic studies showed that inhibition of PI3K/Akt signaling, or its upstream mediator STAT5 can prevent palmitic acid-induced SLAMF3 upregulation on T cells. Interpretation: These results indicate that SLAMF3 upregulation is associated with T cell activation and cytokine production in T2D patients, and suggest that elevated saturated fatty acids in T2D patients may induce SLAMF3 upregulation on T cells via activation of the STAT5-PI3K/Akt signaling pathway. Funding Statement: This work was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030303), Chinese MOST (2015CB964400 and 2017YFA0104402), NSFC (81570145, 81870091, 91642208, 91742107, and 81501279), Plan B for Bethune Project of Jilin University (2015210), an innovation capability project of Jilin Province Development and Reform Commission (2017C019), an open topic of Jilin Province Science and Technology Agency (20170623092TC-01 & 20180623083TC-01). Declaration of Interests: The author(s) declare no competing financial interests. Ethics Approval Statement: Protocols involved in the use of human samples were approved by the Institutional Review Board, and all of the experiments were performed in accordance with the protocols.