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

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, as T cells primed under such conditions were found to acquire a unique phenotype and function. Herein, we found a significant upregulation of signaling lymphocytic activation molecule family member 3 (SLAMF3) expression 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. Significantly increased SLAMF3 expression was seen in T2D patient T cells that produce IFN-γ or IL-17 upon short (4-h) stimulation, compared to non-cytokine-producing T cells. In line with this finding, SLAMF3 high T cells were significantly more sensitive than SLAMF3 low T cells to TCR stimulation with anti-CD3/CD28 antibodies. Furthermore, treatment with palmitic acid (PA) led to significant upregulation of SLAMF3 on human T cells primed by anti-CD3/CD28 antibodies and on Jurkat cells, a human T-cell line. RNA sequencing revealed strong activation of the PI3K/Akt signaling pathway in T cells that were primed with PA. Further mechanistic studies showed that inhibition of PI3K/Akt signaling, or its upstream mediator STAT5 can prevent PA-induced SLAMF3 upregulation on T cells. 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.

Long Chain Fatty Acids as Modulators of Immune Cells Function: Contribution of FFA1 and FFA4 Receptors

“…Jeffery et al, 1996Jeffery et al, , 1997Cury-Boaventura et al, 2004 ↑ calcium, PLC, ERK1/2, p38 MAPK, Akt, NF-κB, ROS, TX, TNF-α, MMP-9, COX-2, IL-8, NETs, IL-1β, CINC-2αβ, VEGFα in neutrophils Vaughan and Walsh, 2005;Pereira et al, 2008;Rodrigues et al, 2010;Hidalgo et al, 2011;Manosalva et al, 2015;Mena et al, 2016;Alarcon et al, 2020 ↓ IL-1β, IL-6, IL-10, ERK1/2, JNK, p38 MAPK, NF-κB; ↑ TNF-α, IL-6, Ccl2 and IL-1β and ROS in macrophages Rahman et al, 2006;Rybicka et al, 2011;Stachowska et al, 2011;Magdalon et al, 2012;Kain and Halade, 2019;Kim et al, 2020 Palmitic acid ↑ STAT5, PI3K/Akt, JNK, ERK1/2, SLAMF3, IFN-γ, TNF-α, IL-6, IL-8, IL-1β, IL-2, IL-10, proliferation, SLAMF3, IL17A in T-cells. Karsten et al, 1994;Lima et al, 2002;Tinahones et al, 2004;Stentz and Kitabchi, 2006;Gorjao et al, 2007;Takahashi et al, 2012;Zhou et al, 2019;Torres-Hernandez et al, 2020 ↑ ERK1/2, Akt, NETs, ROS, chemotaxis in neutrophils. Wanten et al, 2002;Khan et al, 2018;Tam et al, 2020 ↑ adhesion, apoptosis, NLRP3, NO, IL-1β, IL-6, TNF-α, NF-κB, JNK, MKK4/7, IL-10, CCL2, IFN-γ M1 polarization, CD36; ↓ phagocytosis in macrophages.…”

The Influence of Dietary Fatty Acids on Immune Responses

“…While UFAs have shown anti-inflammatory effects, SFAs, such as PA, have been described as an essential factor driving T-cell activation. PA-treated T cells show the activation of Phosphoinositide 3-kinase/Akt signaling, a pathway known to be rapidly activated upon T-cell priming [99][100][101]. In addition, PA treatment significantly upregulates, via JAK/STAT5 pathway, the expression of signaling lymphocyte-activation molecule family member 3, a receptor strongly associated with T cell activation and increases transcription of several inflammatory genes, including TNF-α, IL-1β, IL-6, IFN-γ, IL17A and IL-2 [100,102].…”

“…PA-treated T cells show the activation of Phosphoinositide 3-kinase/Akt signaling, a pathway known to be rapidly activated upon T-cell priming [99][100][101]. In addition, PA treatment significantly upregulates, via JAK/STAT5 pathway, the expression of signaling lymphocyte-activation molecule family member 3, a receptor strongly associated with T cell activation and increases transcription of several inflammatory genes, including TNF-α, IL-1β, IL-6, IFN-γ, IL17A and IL-2 [100,102]. T cells cultured in the presence of PA show the increased expression of the inflammatory marker CD69 [102] and reduced levels of C-C chemokine receptor type 7 and L-selectin [99], suggesting the acquisition of an effector phenotype.…”

Dietary Fatty Acids at the Crossroad between Obesity and Colorectal Cancer: Fine Regulators of Adipose Tissue Homeostasis and Immune Response

“…According to what was reported for innate immunity cells, saturated and unsaturated FA were shown to exert opposite effects on signalling pathways, gene expression and effector functions of cells participating to adaptive immunity, mostly T lymphocytes ( Figure 1 ). Exposure of naive T lymphocytes to PA was found to induce the expression of signalling lymphocytic activation molecule family member 3 ( SLAMF3 ), a molecule found upregulated in T cells from T2DM patients and associated with their ability to produce IFN -γ and IL-17 [ 111 ]. PA-induction of SLAMF3 required the activation of STAT5 and PI3K/AKT signalling pathway, in keeping with previous data showing the key role of this pathway in PA-induced Th1/Th17 cell commitment [ 134 ].…”