AI Article Synopsis

  • The study explores how dendritic cells (DCs), particularly monocyte-derived DCs (MoDCs), can be used for tumor treatment or autoimmune conditions by manipulating their responses.
  • It finds that lower cell concentrations lead to more inflammatory responses and better ability to stimulate the immune system, while higher concentrations promote anti-inflammatory properties and flexibility to differentiate into other cell types.
  • The inhibitory effects of high cell density are mediated by lactic acid, which impacts DC differentiation, suggesting a new way to enhance the effectiveness of DC vaccines by controlling culture conditions.

Article Abstract

The demand for controlling T cell responses via dendritic cell (DC) vaccines initiated a quest for reliable and feasible DC modulatory strategies that would facilitate cytotoxicity against tumors or tolerance in autoimmunity. We studied endogenous mechanisms in developing monocyte-derived DCs (MoDCs) that can induce inflammatory or suppressor programs during differentiation, and we identified a powerful autocrine pathway that, in a cell concentration-dependent manner, strongly interferes with inflammatory DC differentiation. MoDCs developing at low cell culture density have superior ability to produce inflammatory cytokines, to induce Th1 polarization, and to migrate toward the lymphoid tissue chemokine CCL19. On the contrary, MoDCs originated from dense cultures produce IL-10 but no inflammatory cytokines upon activation. DCs from high-density cultures maintained more differentiation plasticity and can develop to osteoclasts. The cell concentration-dependent pathway was independent of peroxisome proliferator-activated receptor γ (PPARγ), a known endogenous regulator of MoDC differentiation. Instead, it acted through lactic acid, which accumulated in dense cultures and induced an early and long-lasting reprogramming of MoDC differentiation. Our results suggest that the lactic acid-mediated inhibitory pathway could be efficiently manipulated in developing MoDCs to influence the immunogenicity of DC vaccines.

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Source
http://dx.doi.org/10.4049/jimmunol.1300772DOI Listing

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