Immunomodulatory Functions of Adipose Mesenchymal Stromal/Stem Cell Derived from Donors with Type 2 Diabetes and Obesity on CD4 T cells

Abstract

<p>For adipose stromal/stem cell (ASCs)-based immunomodulatory therapies, it is important to study how donor characteristics, such as obesity and type 2 diabetes (T2D), influence ASCs efficacy. Here, ASCs were obtained from two groups, donors and T2D and obesity (dASCs) or nondiabetic donors with normal-weight (ndASCs), and then cultured with anti-CD3/CD28-stimulated allogeneic CD4 T cells. ASCs were studied for the expression of the immunomodulators CD54, CD274, and indoleamine 2, 3 dioxygenase 1 (IDO) in inflammatory conditions. CD4 T cells cultured alone or in cocultures were assessed to evaluate proliferation, activation marker surface expression, apoptosis, the regulatory T cells (Tregs; CD4 + CD25 high FOXP3 +) frequency, and intracellular cytokine expression using flow cytometry. Modulation of T-cell subset cytokines was explored via ELISA. In inflammatory conditions, the expression of CD54, CD274 and IDO was significantly upregulated in ASCs, with no significant differences between ndASCs and dASCs. dASCs retained the potential to significantly suppress CD4 T-cell proliferation, with a slightly weaker inhibitory effect than ndASCs, which was associated with significantly reduced abilities to decrease IL-2 production and increase IL-8 levels in cocultures. Such attenuated potentials were significantly correlated with increasing body mass index. dASCs and ndASCs comparably reduced CD4 T-cell viability, HLA-DR expression, and interferon-gamma production and conversely increased CD69 expression, the Tregs percentage, and IL-17A production. Considerable amounts of the immunomodulators prostaglandin E2 (PGE2) and IL-6 were detected in the conditioned medium of cocultures. These findings suggest that ASCs obtained from donors with T2D and obesity are receptive to the inflammatory environment and able to modulate CD4 T cells accordingly.</p>