Adhesive substrates modulate the activation and stimulatory capacity of non-obese diabetic mouse-derived dendritic cells.

摘要

It is known that adsorbed adhesive proteins on implanted biomaterials modulate inflammatory responses; however, modulation of dendritic cell (DC) responses upon interaction with adhesive proteins has only begun to be characterized. DCs are specialized antigen-presenting cells that modulate both innate and adaptive immune responses. Previously we have shown that the activation and stimulatory capacity of DCs derived from C57BL6/j mice is differentially modulated by adhesive substrates. Here we extend our investigation of adhesive substrate modulation of DC responses to consider the case where the DCs had maturational defects associated with diabetes. Understanding the adhesive responses of DCs in diabetics is potentially important for immunotherapy and tissue engineering applications. In this work we use the non-obese diabetic (NOD) mouse, an established animal model for type 1 diabetes, to generate DCs (NOD-DCs). We demonstrate that NOD-DCs cultured on different adhesive substrates (collagen, fibrinogen, fibronectin, laminin, vitronectin, albumin and serum) respond with substrate-dependent modulation of the surface expression of the stimulatory molecule MHC-II and the co-stimulatory molecules CD80 and CD86 and production of the cytokines IL-12p40 and IL-10. Furthermore, the capacity of NOD-DCs to stimulate CD4(+) T-cell proliferation and cytokine production (IL-4 and IFN-gamma) showed substrate-dependent modulation. Specifically, NOD-DCs cultured on vitronectin induced the highest IL-12p40 production, whereas collagen induced the highest IL-10 production. Dendritic cells cultured on collagen, fibrinogen and serum-coated substrates stimulated the highest CD4(+) T-cell proliferation. It was further determined that DCs cultured on vitronectin induced the highest percent population of IL-4-producing T-cells and DCs cultured on a fibronectin-coated substrate induced the highest expression of IFN-gamma in T-cells. Pearson's correlation analysis revealed high correlations between T-cell proliferation and DC expression level of CD80 and T-cell production of IL-4 and DC production of IL-10. This demonstration of substrate-based control of NOD-DC activatory and stimulatory capacity, distinct from non-diabetic B6-DC responses, establishes the field of adhesive modulation of immune cell responses and informs the rational design of biomaterials for patients with type 1 diabetes.