title: Dendritic cell reprogramming by endogenously produced lactic acid.
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.
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm 17177, Sweden.
authors: Aikaterini
authors: A
authors: Nasi
authors: Tünde
authors: T
authors: Fekete
authors: Akilan
authors: A
authors: Krishnamurthy
authors: Stuart
authors: S
authors: Snowden
authors: Eva
authors: E
authors: Rajnavölgyi
authors: Anca I
authors: AI
authors: Catrina
authors: Craig E
authors: CE
authors: Wheelock
authors: Nancy
authors: N
authors: Vivar
authors: Bence
authors: B
authors: Rethi
mesh_terms: D019898:Autocrine Communication / Q000276:immunology*; D018929:Cell Culture Techniques / Q000379:methods*; D002454:Cell Differentiation / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D019344:Lactic Acid / Q000096:biosynthesis* / Q000276:immunology; D016133:Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D019344:Lactic Acid